Virology (2022-2023) PDF

Virology: Chapter 1: The Virus Dr Anna Maria Henaine PharmD, MB, MBA, PhD  Introduction  Viruses are too small to be seen with a light microscope.  Unlike other infectious → obligate intracellular parasites  absolutely require living host cells in order to multiply 1. Filtera...

Virology: Chapter 1: The Virus Dr Anna Maria Henaine PharmD, MB, MBA, PhD  Introduction  Viruses are too small to be seen with a light microscope.  Unlike other infectious → obligate intracellular parasites  absolutely require living host cells in order to multiply 1. Filterable agents (small size pass through filters (retain back bacteria) 2. Obligate intracellular parasites. 3. Contain a single type of nucleic acid: either DNA or RNA (not both) 4. The virion* of the virus particle consists of a nucleic acid genome packaged into a protein coat (capsid), which itself is sometimes enclosed by an envelope of lipid, proteins, and carbohydrates known as envelope. 5. Multiply inside the living cells by using the synthesizing machinery of the host cell 6. Replicate by the assembly of the individual components and do not replicate by division, such as binary fission. 7. Few or no enzymes for their own metabolism.  They always use host cell machinery to produce their components, such as viral messenger RNA (mRNA), protein, and identical copies of the genome (ribosomes of the bacteria)  The viruses that infect bacteria are known as bacteriophages or phages. Bacteria vs viruses Structure of a virus  The virion consists of a nucleic acid core, the genome, surrounded by a protein coat, the capsid  The capsid together with the enclosed nucleic acid is known as the nucleocapsid.  Some viruses are surrounded by envelopes 1-The Capsid  The nucleic acid of a virus is surrounded by a protein coat called the capsid.  Each capsid is composed of a large number of protein subunits (polypeptides) called capsomeres  The polypeptide molecules composing the capsomeres are of a single type in some viruses, while in other viruses several types may be present.  The arrangement of capsomeres is characteristic of a particular type of virus.  Functions of capsid: ▪ Impenetrable shell around the nucleic acid core. ▪ Facilitates entry of viral genome into the host cells by adsorbing readily to cell surfaces. ▪ Protects its nucleic acid from the activity of nuclease enzymes in biological fluids and thereby facilitates attachment of virus to target cells in the host.  Classification  On the basis of capsid structure, the viruses can be classified into different morphological types as follows:  Helical viruses: rod-like and may be rigid or flexible. The viral genome is found within hollow cylindrical capsid that has a helical structure. Examples: rabies virus, Ebola hemorrhagic virus  Polyhedral viruses: They appear as many sided viruses. The viruses consist of capsids in the shape of an icosahedron. It is a regular polyhedron with 20 triangular faces. The capsomere of each face forms an equilateral triangle. Adenovirus is an example  Enveloped viruses: The helical and polyhedral viruses when covered by envelope are called as enveloped helical or enveloped polyhedral viruses, respectively. Influenza virus is an example of enveloped helical virus, and herpes simplex virus is an example of enveloped polyhedral virus.  Complex viruses: Some viruses, such as viruses of bacteria (bacteriophages), have complicated structures and are called complex viruses. Examples  2- The Envelope  All of the negative-stranded RNA viruses are enveloped.  Viruses that lack envelope are called non-enveloped or naked viruses.  The virion envelope usually consists of lipids, proteins, and glycoproteins.  The viral envelope does not contain any cellular proteins, even though viruses are released from the host cell by an extrusion process that coats the virus with a layer of host cell plasma membrane that becomes the viral envelope.  In most cases, the envelope contains proteins that are determined and encoded by viral nucleic acid.  The lipid component of the envelope is usually of host cell origin.  Depending on the virus, the envelopes of the viruses may or may not be covered by spikes [glycoprotein-like projections on the outer surface of the envelope. Most spikes act as viral attachment protein (VAP)].  3- Viral Symmetry Depending on the arrangement of the capsid around the nucleic acid core (genome): ❖ Icosahedral symmetry: Two types of capsomeres = the icosahedral capsule. o They are the pentagonal capsomeres or the vertices (pentons) and hexagonal capsomeres making up the facets (hexons) o There are always 12 pentons, but the number of hexons varies with the virus group. ✓ Each penton has fivefold symmetry (pentamer or pentagon) in the shape of an equilateral triangle. This pentamer symmetry is found in simple viruses, such as the picornaviruses and parvoviruses. ✓ The hexamer symmetry is usually found in large capsid virions, such as herpesviruses and adenoviruses. ❖ Helical symmetry: The nucleic acid and the capsomeres = spherical or spiral tube. Most negative-stranded RNA viruses. ❖ Complex symmetry: Some viruses may not exhibit either icosahedral or helical symmetry => complex symmetry. For example, poxvirus 4- Viral Nucleic Acid, Proteins and Lipids ❑ Viral nucleic acid  The genome of the virus consists of either DNA or RNA but never both  The DNA can be single stranded or double stranded.  Depending on the virus, the DNA can be linear or circular.  The RNA can be either positive sense (+) like mRNA or negative sense (-), double stranded (+/-), or ambiguous (containing + and - regions of RNA attached to it).  In some RNA viruses, such as the influenza virus, the RNA genome is in several separate segments, each segment encoding an individual gene.  The total amount of nucleic acid may vary from a few thousand nucleotides to as many as 250,000 nucleotides. ❑ Viral proteins and lipids  Viruses contain proteins, which constitute capsids. The viral protein protects the nucleic acid as well as determines the antigenic specificity of the virus.  In addition, the enveloped viruses contain lipids, which are derived from the host cell membrane. family and nature Properties of Human DNA Viruses (Deoxyriboviruses) Properties of Human RNA Viruses (Riboviruses)  Viral Multiplication  Virus requires host cells to multiply  Utilizes host cell’s metabolic machinery  Single virion can produce several to thousands of new viruses in a single host cell  2 types of multiplication: ✓ Lytic cycle: ▪ Ends with death and lysis of the cell ▪ T-even bacteriophage ✓ Lysogenic cycle ▪ Host cell remains alive ▪ Bacteriphage λ Stages in a viral replication cycle Stages in a viral replication cycle  Lytic Cycle  Adsorption (attachment): T4 attaches by means of specific tail fiber proteins to complementary receptors on the host cell’s surface. The nature of these receptors is one of the main factors in determining a virus’s host specificity.  Penetration: The enzyme lysozyme, present in the tail of the phage, weakens the cell wall at the point of attachment, and a contraction of the tail sheath of the phage causes the core to be pushed down into the cell, releasing the viral DNA into the interior of the bacterium. The capsid remains entirely outside the cell  Replication: Phage genes cause host protein and nucleic acid synthesis to be switched off, so that all of the host’s metabolic machinery becomes dedicated to the synthesis of phage DNA and proteins. Host nucleic acids are degraded by phage-encoded enzymes, thereby providing a supply of nucleotide building blocks. Host enzymes are employed to replicate phage DNA, which is then transcribed into mRNA and translated into protein.  Assembly: Once synthesized in sufficient quantities, capsid and DNA components assemble spontaneously into viral particles. The head and tail regions are synthesized separately, then the head is filled with the DNA genome, and joined onto the tail.  Release: Phage-encoded lysozyme weakens the cell wall, and leads to lysis of the cell and release of viral particles; these are able to infect new host cells, and in so doing recommence the cycle.  The one-step growth curve During the early phase of infection, the host cell contains components of phage, but no complete particles. This period is known as the eclipse period. The time which elapses between the attachment of a phage particle to the cell surface and the release of newly-synthesized phages is the latent period (“burst time”); for T4 under optimal conditions, this is around 22 minutes. The Viral Life Cycle Main stages in a viral replication cycle  Lysogenic replication cycle  Phages such as T4, which cause the lysis of their cells, are termed virulent phages.  Temperate phages, in addition to following a lytic cycle, undergo an alternative form of growth cycle=>the phage DNA actually becomes incorporated into the host’s genome as a prophage  In this condition of lysogeny, the host cell suffers no harm [action of repressor proteins, encoded by the phage, prevents most of the other phage genes being transcribed].  These genes are, however, replicated along with the bacterial chromosome, so all the bacterial offspring contain the incorporated prophage. The lysogenic state is ended when the survival of the host cell is threatened, usually by an environmental factor such as UV light or a chemical mutagen.  Inactivation of the repressor protein allows the phage DNA to be excised, and adopt a circular form in the cytoplasm  it initiates a lytic cycle, resulting in destruction of the host cell.  An example of a temperate phage is bacteriophage λ (Lambda), which infects certain strains of E. coli. Bacterial strains that can incorporate phage DNA in this way are termed lysogens. Replication Cycles In Animal Viruses  Viruses that infect multicellular organisms such as animals may be specific not only to a particular organism, but also to a particular cell or tissue type.  Known as the tissue tropism of the virus [due to the fact that attachment occurs via specific receptors on the host cell surface].  The growth cycles of animal viruses have the same main stages as described for , but may differ a good deal in some of the details.  Most of these variations are a reflection of differences in structure between bacterial and animal host cells. Bacteriophage and Viral Multiplication Compared what is the difference between lysogeny and latency  Replication cycles in animal viruses  Adsorption and penetration ✓ Animal viruses do not have the head and tail structure of phages  different attachment ✓ The specific interaction (host) = via some component of the capsid, or, in the case of enveloped viruses, by special structures such as spikes (peplomers). ✓ Viral attachment sites can frequently be blocked by host antibody molecules; however some viruses (rhinoviruses) have overcome this by having their sites situated in deep depressions, inaccessible to the antibodies. ✓ Whereas bacteriophages inject their nucleic acid component from the outside, the process in animal viruses is more complex, a fact reflected in the time taken for completion of the process. ✓ Animal viruses do not have to cope with a thick cell wall, and in many such cases the entire virion is internalized  extra step of uncoating, a process carried out by host enzymes. ✓ Many animal viruses possess an envelope; such viruses are taken into the cell either by fusion with the cell membrane, or by endocytosis ✓ While some non-enveloped types release only their nucleic acid component into the cytoplasm, others require additionally that virus-encoded enzymes be introduced to ensure successful replication. Replication (DNA Viruses)  Replication ✓ The DNA of animal cells, unlike that of bacteria, is compartmentalized within a nucleus, and it is here that replication and transcription of viral DNA generally occur. ✓ Messenger RNA then passes to ribosomes in the cytoplasm for translation ✓ In the case of viruses with a ssDNA genome, a double-stranded intermediate is formed, which serves as a template for mRNA synthesis.  Assembly ✓ Translation products are finally returned to the nucleus for assembly into new virus particles.  Release: Naked (non-enveloped) viruses are generally released by lysis of the host cell. In the case of enveloped forms, release is more gradual. The host’s plasma membrane is modified by the insertion of virus-encoded proteins, before engulfing the virus particle and releasing it by a process of budding. ✓ This can be seen as essentially the reverse of the process of internalization by fusion  Replication (RNA Viruses)  Replication of RNA viruses occurs in the cytoplasm of the host;  Depending on whether the RNA is single- or double-stranded, and (+) or (−) sense, the details differ.  The genome of a (+) sense single stranded RNA virus functions directly as an mRNA molecule, producing a giant polyprotein, which is then cleaved into the various structural and functional proteins of the virus.  In order for the (+) sense RNA to be replicated, a complementary (−) sense strand must be made, which acts as a template for the production of more (+) sense RNA  The RNA of a (−) sense RNA virus must first act as a template for the formation of its complementary sequence by a virally encoded RNA polymerase.  The (+) sense RNA so formed has two functions: (i) to act as mRNA and undergo translation into the virus’s various proteins, and (ii) to act as template for the production of more genomic (−) sense RNA  Double-stranded RNA viruses are all segmented. They form separate mRNAs for each of their proteins by transcription of the (−) strand of their genome. → later form an aggregate (subviral particle) with specific proteins* Biosynthesis of DNA and RNA  Assembly and Release of Progeny Viruses  Assembly of nucleocapsids generally takes place in the host cell compartment where the viral nucleic acid replication occurs (cytoplasm (most RNA viruses) and nucleus (most DNA viruses))  For DNA viruses, this requires that capsid proteins be transported from their site of synthesis (cytoplasm) to the nucleus. The various capsid components begin to self-assemble, eventually associating with the nucleic acid to complete the nucleocapsid. 1. Naked (unenveloped) viruses  the virion is complete at this point  Release of progeny is usually a passive event resulting from the disintegration of the dying cell and, therefore, may be at a relatively late time after infection. 2. Enveloped viruses  virus-specific glycoproteins are synthesized and transported to the host cell membrane in the same manner as cellular membrane proteins. When inserted into the membrane  displace the cellular glycoproteins, resulting in patches on the cell surface that have viral antigenic specificity. The cytoplasmic domains of these proteins associate specifically with one or more additional viral proteins (matrix proteins) to which the nucleocapsids bind. Final maturation then involves envelopment of the nucleocapsid by a process of “budding”  Consequences of Viral Replication  Progeny virus are released continuously while replication is proceeding within the cell and ends when the cell loses its ability to maintain the integrity of the plasma membrane.  With most enveloped viruses, all infectious progeny are extracellular. The exceptions are those viruses that acquire their envelopes by budding through internal cell membranes such as those of the endoplasmic reticulum or nucleus. Viruses containing lipid envelopes are sensitive to damage by harsh environments and, therefore, tend to be transmitted by the respiratory, parenteral, and sexual routes. Non-enveloped viruses are more stable to hostile environmental conditions and often transmitted by the fecal-oral route  Effects of Viral Infection on the Host Cell  The response of a host cell to infection by a virus ranges from: 1) Little or no detectable effect; to 2) Alteration of the antigenic specificity of the cell surface due to presence of virus glycoproteins; to 3) Latent infections that, in some cases, cause cell transformation; or, ultimately, to 4) Cell death due to expression of viral genes that shut off essential host cell functions  Effects of Viral Infection on the Host Cell 1. Viral infections in which no progeny virus are produced  infection = abortive. An abortive response to infection is commonly caused by: 1) a normal virus infecting cells that are lacking in enzymes, promoters, transcription factors, or other compounds required for complete viral replication, in which case the cells are referred to as non-permissive; 2) infection by a defective virus of a cell that normally supports viral replication (by a virus that itself has genetically lost the ability to replicate in that cell type); or 3) death of the cell as a consequence of the infection, before viral replication has been completed. 2. Viral infections in which the host cell may be altered antigenically but is not killed, although progeny virus are released => host cell is permissive, and the infection is productive. Viral replication and release neither kills the host cell nor interferes with its ability to multiply and carry out differentiated functions  The infection is persistent. 3. Viral infections that result in a latent viral state in the host cell (persistence of the viral genome inside a host cell with no production of progeny virus). Such latent viruses can be reactivated months or years in the future, leading to a productive infection. Some latently infected cells contain viral genomes that are stably integrated into a host cell chromosome  alterations in the host cell surface; cellular metabolic functions; and, significantly, cell growth and replication patterns. Such viruses may induce tumors in animals, in which case they are said to be tumor viruses, and the cells they infect are transformed. 4. Viral infections resulting in host cell death and production of progeny virus: the typical result of a productive (progeny-yielding) infection by a cytocidal virus is the shutoff of much of the cell’s macromolecular syntheses causing the death of the cell  lytic infection. Effects of viral infection on a host cell  Pathogenic Properties of Virus  Viruses have mechanisms to evade host defenses viruses grow inside host cells to hide from immune defense  Kill immune cells (HIV – TH Cells)  Cytopathic effects: The visible effects of viral infection on host cell. Some effects will kill the cell and some will just change the cells  Viruses stop DNA, RNA and/or protein synthesis (Herpes virus block mitosis)  Lysosomal autolysis of host cells (Influenza: bronchiolar epithelium)  Production of inclusion bodies (visible viral parts inside the cell) can identify a particular virus (Rabies virus: Negri bodies)  Syncytium formation (neighboring cells fuse together) (Varicella Zoster virus)  Change in cell function (Measles, production of interferons by host cell (triggers host immune response), induce antigenic changes on host cell surface (triggers destruction of infected cell by host immune response))  Induce chromosomal changes, cell transformation: may activate or deliver oncogenes resulting in loss of contact inhibition (cancer) (Papilloma virus) Common Pathogenic Viruses Genome Family Example Virus Clinical Features Poxviridae Orthopoxvirus Skin papules, pustules, lesions dsDNA, enveloped Poxviridae Parapoxvirus Skin lesions Cold sores, genital herpes, sexually Herpesviridae Simplexvirus transmitted disease Adenoviridae Atadenovirus Respiratory infection (common cold) Genital warts, cervical, vulvar, or dsDNA, naked Papillomaviridae Papillomavirus vaginal cancer Gastroenteritis severe diarrhea Reoviridae Reovirus (stomach flu) Adeno-associated Parvoviridae Respiratory tract infection dependoparvovirus A ssDNA, naked Adeno-associated Parvoviridae Respiratory tract infection dependoparvovirus B dsRNA, naked Reoviridae Rotavirus Gastroenteritis Picornaviridae Enterovirus C Poliomyelitis Upper respiratory tract infection +ssRNA, naked Picornaviridae Rhinovirus (common cold) Picornaviridae Hepatovirus Hepatitis Togaviridae Alphavirus Encephalitis, hemorrhagic fever Togaviridae Rubivirus Rubella +ssRNA, enveloped Acquired immune deficiency syndrome Retroviridae Lentivirus (AIDS) Filoviridae Zaire Ebolavirus Hemorrhagic fever −ssRNA, enveloped Orthomyxoviridae Influenzavirus A, B, C Flu Rhabdoviridae Lyssavirus Rabies  Viruses associated with Respiratory Infections: Coryza: Rhinoviruses (30-50%), Coronaviruses (10-30%) Influenza: Influenza virus Croup: Parainfluenza viruses Bronchiolitis: RSV Bronchopneumonia: RSV, Influenza Virus, Adenoviruses Replication Cycles In Plant Viruses  Viral infections of plants can be spread by one of two principal pathways. ❑ Horizontal transmission : introduction of a virus from the outside, and typically involves insect vectors, which use their mouth parts to penetrate the cell wall and introduce the virus. This form of transmission can also occur by means of inanimate objects such as garden tools. ❑ Vertical transmission the virus is passed from a plant to its offspring, either by asexual propagation or through infected seeds.  The majority of plant viruses have an RNA genome (DNA forms : caulimoviruses)  Replication is similar to that of animal viruses, depending on the nature of the viral genome.  An infection only becomes significant if it spreads throughout the plant (systemic infection).  Viral particles do this by moving through the plasmodesmata, naturally occurring cytoplasmic strands linking adjacent plant cells.  PLANT VIRUSES  VIROIDS: Many times smaller than the smallest virus, and consist solely of a small circle of ssRNA containing some 300-400 nucleotide bases and no protein coat. ❖ Enzymes in the host’s nucleus are used to replicate the RNA, which does not appear to be translated into protein. ❖ A viroid is a plant pathogen that comprises only ssRNA and does not code for a protein product (Ex: Potato spindle tuber viroid, Coconut, cadang cadang viroid).  PRIONS: (=proteinaceous infectious particle) self-replicating proteins responsible for a range of neurodegenerative disorders in humans and mammals. Transmitted: surgical instruments and consumption of infected meat/nervous tissue ❖ Bovine spongiform encephalopathy(BSE, ‘mad cow disease’)and its human equivalent, Creutzfeldt-Jakob disease. Classification of Viruses Non-Enveloped DNA viruses (Naked) 1-Non-enveloped DNA viruses: PAPOVAVIRDAE Icosahedral nucleocapsids; contain supercoiled, double-stranded, circular DNA. Basic differences in genome complexity and regulation of gene expression 2 subfamilies: ▪ Papillomavirinae ▪ Polyomavirinae. Papovaviruses induce both lytic infections and either benign or malignant tumors, depending on infected cell type.  A- PAPILLOMAVIRINAE  Hyperplastic epithelial lesions in their host species.  >150 types of human papillomaviruses (HPVs) are now recognized, based on differences in the DNA sequences of certain well characterized virus genes.  HPVs exhibit great tissue and cell specificity, infecting only surface epithelia of skin and mucous membranes.  Transmission of HPV infection requires direct contact with infected individuals (sexual contact) or with contaminated surfaces (fomites) such as communal bathroom floors. Also transmitted from mother to infant during passage down the birth canal. Also abrasions  The HPVs within each of these tissue-specific groups have varying potential for causing malignancies: 1) Small number of virus types (specifically, types 16 and 18) => produce lesions with a high risk of progression to malignancy such as in cervical carcinoma; 2) Others produce mucosal lesions that progress to malignancy with lower frequency => anogenital warts (condyloma acuminata, a common sexually transmitted disease) and laryngeal papillomas (the most common benign epithelial tumors of the larynx); 3) Associated only with benign lesions (common, flat, and plantar warts).  B- POLYOMAVIRINAE  Capacity to transform normal cells in culture and to induce tumors in species other than those in which they are normally found in nature.  “Polyoma” means many (poly-) tumor (-oma).  3 human polyomaviruses: BK, JC, and Merkel cell polyomaviruses  JCV has been associated with progressive multifocal leukoencephalopathy (PML), a rare, fatal, demyelinating disease that occurs only in patients with impaired immune function (AIDS).  BKV can cause cystitis in this same population.  MCV : Merkel cell carcinoma, a rare and aggressive form of skin cancer.  The human polyomaviruses BKV and JCV are transmitted by droplets from the upper respiratory tract of infected persons and, possibly, through contact with their urine. Infection with these viruses usually occurs in childhood. Specific antibody to one or both human polyomaviruses is present in 70 to 80 % of the adult population.  Both BKV and JCV spread from the upper respiratory tract to the kidneys, where they may persist in an inactive state in the tubular epithelium of healthy individuals.  Polyomaviruses follow the basic pattern of DNA virus genome replication and gene expression in the nucleus. The enzymes and precursors synthesized in preparation for cellular DNA synthesis are made available for synthesis of viral DNA. This productive cycle leads to viral multiplication and, ultimately, to death of the host cell. 2-Non-enveloped DNA viruses: ADENOVIRIDAE  Non-enveloped, icosahedral ( hexon capsomers making up the triangular faces of the icosahedron, with a penton capsomer at each of the vertices) viruses containing double- stranded linear DNA  Cause diseases such as respiratory tract infections, gastroenteritis, and conjunctivitis.  Large group of related viruses commonly infecting humans, other mammals, and birds.  > 50 serotypes of human adenoviruses are known, and antibody surveys have shown that most individuals have been infected by several different types by adulthood.  Most adenoviruses are primarily agents of respiratory disease, transmitted via the respiratory route. May also replicate efficiently and asymptomatically in the intestine, and can be isolated from stool well after respiratory disease symptoms have ended as well as from the stools of healthy persons.  Ocular infections are transmitted by direct inoculation of the eye by virus-contaminated hands, ophthalmologic instruments, or bodies of water in which groups of children swim together.  ADENOVIRIDAE  Clinical significance corticosteroid ktr 5tra bs ykun fi virus 1. Respiratory tract diseases: acute febrile pharyngitis (cough, sore throat, nasal congestion, and fever). Some adenovirus types tend additionally to produce conjunctivitis pharyngoconjunctival fever : prevalent in school-aged children and occurs both sporadically and in outbreaks, often within family groups or in groups using the same swimming facility (“swimming pool conjunctivitis”). The respiratory syndromes may progress to true viral pneumonia(mortality rate of about 10 % in infants). 2. Ocular diseases: In addition to the conjunctivitis that sometimes accompanies the upper respiratory syndrome , a similar follicular conjunctivitis may occur as a separate disease: self-limiting and no permanent sequelae. A more serious infection is epidemic keratoconjunctivitis, which involves the corneal epithelium, and may be followed by corneal opacity lasting several years [transmission via shared towels or ophthalmic solutions, person-to-person contact, and improperly sterilized ophthalmologic instruments]. 3. Gastrointestinal diseases: Most human adenoviruses multiply in the GI tract and can be found in stools. Generally asymptomatic. Two serotypes have been associated specifically with infantile gastroenteritis. Adenovirus infections have been estimated to account for 5 to 15 % of all viral diarrheal disease in children. dont study diagnosis 3-Non-enveloped DNA viruses: PARVOVIRIDAE  The smallest of the DNA viruses.  Non-enveloped and icosahedral, with single-stranded, linear DNA.  A human parvovirus, B19, has been isolated and identified as the cause of transient aplastic crisis in patients with sickle cell disease and implicated in adult acute polyarthritis, common childhood disease erythema infectiosum and fetal death in pregnant women experiencing a primary infection.  Divided into 2 genera, based on whether their ability to replicate requires coinfection with a helper DNA virus, or if they are capable of independent replication (“autonomous parvoviruses”).  Members of the first group  Adeno Associated Viruses (AAVs), because they are usually found in infected cells in combination with a helper adenovirus.  Transmission by the respiratory route.  A specific antibody response occurs rapidly, resulting in suppression of the viremia.  PARVOVIRIDAE  Clinical significance The single human pathogen in this family is the autonomous parvovirus, B19 that was initially isolated from sickle cell disease patients undergoing a transient aplastic crisis, => chronic, progressive bone marrow suppression results from B19 infection of immunocompromised patients unable to mount an immune response capable of eliminating the virus. 1. Erythema infectiosum: 30 to 60% of some human populations have antibodies to B19 => this virus : the causative agent of the common childhood rash, erythema infectiosum (“fifth disease”). The characteristic rash (“slapped cheek” appearance) occurs about 2 weeks after initial exposure, when the virus is no longer detectable. The rash is apparently immune-system mediated. Another complication : acute arthritis that involves joints symmetrically (adults >> children and usually resolves within several weeks). 2. Birth defects: Spontaneous abortion rate is elevated in women having a primary infection during the first trimester, and primary infection during the second or third trimester is associated with some instances of hydrops fetalis. Classification of Viruses  Enveloped DNA Virus: HERPESVIRIDAE  8 human herpesvirus species  Have the ability to enter a latent state following primary infection of their natural host and be reactivated at a later time.  The exact molecular nature of the latency and the frequency and manifestation of reactivation vary with the type of herpesvirus. A. Structure of herpesviruses ❑ Herpesvirus virions consist of an icosahedral capsid enclosed in an envelope derived from the host’s nuclear membrane ❑ Between the envelope and the capsid lies an amorphous proteinaceous material called tegument, which contains virus-encoded enzymes and transcription factors essential for initiation of the infectious cycle, although none of these is a polymerase. ❑ The genome is a single molecule of linear, double-stranded DNA, encoding from 70 to 200 proteins, depending on the species. ❑ Although all members of the family have some genes with homologous functions, there is little nucleotide sequence conservation and little antigenic relatedness between species. Enveloped DNA Virus: HERPESVIRIDAE B. Classification of herpesviruses  Herpesviridae 1. Alphaherpesvirinae: (herpes simplex virus group): These viruses have a relatively rapid, cytocidal or lytic growth cycle and establish dormant or latent infections in nerve ganglia: Herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) and varicella- zoster virus (VZV). 2. Betaherpesvirinae: (cytomegalovirus group): slow replication cycle that results in the formation of characteristic, multinucleated, giant host cells. Latency is established in nonneural tissues, primarily lymphoreticular cells and glandular tissues: Human cytomegalovirus (HCMV) and human herpesviruses types 6 and 7 (HHV-6 and HHV-7) 3. Gammaherpesvirinae: (lymphoproliferative group): replicate in mucosal epithelium and establish latent infections primarily in B cells. They induce cell proliferation in and immortalize lymphoblastoid cells: Epstein-Barr virus (EBV) NB: genome analysis of a virus recovered from cells of Kaposi sarcoma (KS) revealed it to also be a human member of the Gammaherpesvirinae. It has been designated human herpesvirus type 8 (HHV-8). HHV-8 can also establish latency and immortalize endothelial cells  1-Herpes Simplex Virus, types 1 and 2  HSV-1 and HSV-2 are the only human herpesviruses that have a significant degree of nucleotide sequence identity (about 50 %). They share many common features in replication, disease production, and latency.  Transmission is by direct contact with virus-containing secretions or with lesions on mucosal or cutaneous surfaces {Saliva, Skin lesions or Respiratory Secretions}  Primary or recurrent infections in the oropharyngeal region, caused primarily by HSV-1, are accompanied by virus release into saliva, and kissing and saliva-contaminated fingers  In genital tract infections, caused primarily by HSV-2, virus is present in genital tract secretions. => sexual intercourse and passage of newborns through the birth canal of infected mothers are major modes of transmission.  Both HSV-1 and HSV-2 multiply in epithelial cells of the mucosal surface  production of vesicles or shallow ulcers containing infectious virus. In immunocompetent individuals, epithelial infection remains localized because cytotoxic T lymphocytes recognize the HSV-specific antigens on the surface of infected cells and kill these cells before progeny virus has been produced. A lifelong latent infection is usually established in the regional ganglia as a result of entry of infectious virions into sensory neurons that terminate at the site of the infection.  HSV-1 is most commonly found in lesions above the waist, and HSV-2 is more commonly the cause of lesions below the waist. However, HSV-1 can infect the genital tract, causing similar lesions, and, similarly, HSV-2 can cause lesions in the oral cavity.  Herpes Simplex Virus, types 1 and 2 1. Primary infections of the upper body: subclinical, but the most common symptomatic infections of the upper body are gingivostomatitis in young children and pharyngitis or tonsillitis in adults. The painful lesions typically consist of vesicles and shallow ulcers, which are often accompanied by systemic symptoms, such as fever, malaise, and myalgia. Another clinically important site of infection is the eye, in which keratoconjunctivitis can lead to corneal scarring and eventual blindness. If HSV infection spreads to the central nervous system (CNS), it can cause encephalitis, which, if untreated, has a mortality rate estimated to be 70 %. Survivors are usually left with neurologic deficits*. 2. Primary infections of the genital tract: similar to those of the oropharynx. Asymptomatic. When symptomatic (genital herpes), local symptoms include painful vesiculo-ulcerative lesions on the vulva, cervix, and vagina in women and the penis in men. Systemic symptoms of fever, malaise, and myalgia may be more severe than those that accompany primary oral cavity infections. In pregnant women with a primary genital HSV infection, the risk of infecting the newborn during birth is estimated to be 30 to 40% (neonatal herpes)**. 3. Latency: In latently infected cells of the ganglia—HSV-1 in trigeminal ganglia and HSV-2 in sacral or lumbar ganglia—from one to thousands of copies of the viral genome are present as nonintegrated, circular molecules of DNA in the nuclei. A limited number of viral genes are expressed during latency. These transcripts (called LATS for latency-associated transcripts) suppress production of progeny virus.  Herpes Simplex Virus, types 1 and 2 4. Reactivation: Several factors, such as hormonal changes, fever, and physical damage to the neurons, are known to induce reactivation and replication of the latent virus ✓ The newly synthesized virions are transported down the axon to the nerve endings from which the virus is released, infecting the adjoining epithelial cells. Characteristic lesions are thus produced in the same general area as the primary lesions. [Note: Virus replication occurs in only a fraction of the latently infected neurons, and these nerve cells eventually die.] ✓ The presence of circulating antibody does not prevent this recurrence but does limit the spread of virus to surrounding tissue. Sensory nerve symptoms, such as pain and tingling, often precede and accompany the appearance of lesions. ✓ In general, the severity of any systemic symptoms is considerably less than that of a primary infection, and many recurrences are characterized by shedding of infectious virus in the absence of visible lesions. a. Herpes simplex virus type 1: The frequency of oropharyngeal symptomatic recurrences is variable, ranging from none to several a year. The lesions occur as clusters of vesicles at the border of the lips (herpes labialis, or “cold sores” or “fever blisters”) and heal without scarring in 8 to 10 days. b. Herpes simplex virus type 2: Reactivation of HSV-2 genital infections can occur with considerably greater frequency (for example, monthly) and is often asymptomatic but still results in viral shedding. Consequently, sexual partners or newborn infants may be at increased risk of becoming infected resulting from lack of precautions against transmission. The risk of transmission to the newborn is much less than in a primary infection because considerably less virus is shed and the baby has some maternal anti-HSV antibody. This antibody also lessens the severity of the disease if infection does occur. Human Herpesviruses: Basic Properties  Transmission occurs by close contact and maybe venereal in genital herpes. ⇓ Virus enters through defects in skin or mucous membranes & multiply locally. ⇓ Virus enters Cutaneous nerve fibers & is transported to ganglia where it replicates. ⇓ Migration of virus can take place from the ganglia to the Skin and Mucosa causing lesions. ⇓ Virus remains latent in ganglia, particularly of Trigeminal (HSV type 1) & Sacral (HSV type 2) nerves liquid vesicles zONA OR ABSAR SHUWE  VARICELLA-ZOSTER VIRUS (VZV)  Biologic similarities between VZV and HSV → latency established in sensory ganglia and infections are rapidly cytocidal  Primary infections in a non-immune individual (children, teens) causes varicella (“chickenpox”), whereas reactivation of the latent virus (adults), when immunity falls to the ineffective level, causes herpes zoster* (“shingles”)(Varicella and Herpes Zoster caused by a single virus=> VZV)  Only easily spread from person to person by casual contact  Transmission via conjunctiva or respiratory droplets => initial infection of the respiratory mucosa → regional lymph nodes. Progeny virus enter the bloodstream, undergo a second round of multiplication in cells of the liver and spleen, and are disseminated throughout the body by infected mononuclear leukocytes → Endothelial cells of the capillaries → skin epithelial cells  characteristic, virus-containing vesicles of chickenpox that appear from 14 to 21 days after exposure  The infected individual is contagious from 1 to 2 days before the appearance of the exanthema, implying that viruses re-infect cells of the respiratory mucosa near the end of the incubation period  The vesicular fluid from the chickenpox rash is also highly contagious and can be spread to non-immune individuals if it becomes airborne ⇒ Pathogenesis of Varicella – in non-immunized individuals: Virus replicates at the site of entry in the Nasopharynx & in regional lymph nodes ⇓ Primary viremia occurs 4-6 days after infection & disseminates the virus to other organs ⇓ Further replication occurs in viscera, followed by a Secondary viremia ⇓ Rashes appear mainly on trunk sparing the distal parts of the limbs ⇓ It matures very quickly, beginning to crust within 48 hours ⇒ Pathogenesis of Herpes Zoster – reactivation of VZV due to fall in immunity: Virus remaining latent in sensory ganglia Reactivates & travels along the sensory nerve ⇓ Produce zoster lesions in the area of the skin or mucosa supplied by it ⇓ Most common sites are areas innervated by Spinal cord segments D3 to L2 & the trigeminal nerve ⇓ Rashes are unilateral & limited in distribution  VARICELLA-ZOSTER VIRUS (VZV)  Varicella → serious disease in both healthy and immunocompromised adults >> children. Varicella pneumonia is the most common of the serious complications, but fulminant hepatic failure and varicella encephalitis may also result. Primary infection of a pregnant woman may affect the fetus or neonate  Reye syndrome: acute encephalopathy accompanied by fatty liver, can sometimes follow VZV or influenza infections in children. The use of aspirin or other salicylate-containing compounds to treat pain and fever during the viral illness should be avoided and following vaccination against chickenpox.  Recurrent infection* : The incidence of herpes zoster and postherpetic neuralgia can be markedly reduced by using zoster vaccine in appropriate (> 50 years old) populations.  2- HUMAN CYTOMEGALOVIRUS (CMV)  Member of the Betaherpesvirinae subfamily, known as “salivary gland virus”  Replication cycle significantly longer than HSV and VZV, and infected cells typically are greatly enlarged and multinucleated (=>“cytomegalo-”). Incubation period: 4-8 weeks  Only one recognized human species of HCMV, but there are many distinct strains that can be distinguished by antigenic differences as well as by restriction fragment analysis of their genomes.  HCMV is the most common cause of intrauterine infections and congenital abnormalities and a serious threat to immunodeficient and immunosuppressed patients ( retinitis, colitis, pneumonia or encephalitis)  Initial infection with HCMV commonly occurs during childhood. 1. Transmission: Infection in children => asymptomatic. Children continue to shed virus for months in virtually all body fluids, including tears, urine, and saliva. In adults: direct contact => virus can also be transmitted by: 1) sexual means (present in semen and vaginal secretions), 2) organ transplants, 3) blood transfusions and 4) breast milk. In symptomatic cases, kidney tubule epithelium, liver, and CNS, in addition to the respiratory and GI tracts 2. Latency and reactivation: A distinctive feature of HCMV latency is the phenomenon of repeated episodes of asymptomatic virus shedding over prolonged periods. Latency is probably established in monocytes and macrophages  HUMAN CYTOMEGALOVIRUS  In healthy individuals, primary HCMV infection is usually subclinical  Primary infection in adults may result in a mononucleosis syndrome clinically identical to that caused by EBV  Persistent fever, muscle pain, and lymphadenopathy are characteristic , elevated levels of abnormal lymphocytes and liver enzymes.  Two specific situations have greater clinical significance: ▪ Congenital infections [deafness, jaundice, skin rash, pneumonia, splenomegaly, hepatomegaly, microcephaly or seizures…to fetal death*] ▪ Infection of immunocompromised patients [blindness, blurred vision, hepatitis, diarrhea, encephalitis and pneumonia [major cause of death in bone marrow transplant recipients]  3- EPSTEIN-BARR VIRUS  EBV → causative agent of IM or Glandular Fever in young adults.  First human virus related to a malignancy [childhood disease Burkitt lymphoma] and several additional human neoplastic diseases [Nasopharyngeal carcinoma]  Specifically affecting B lymphocyte lineage. Incubation period: 4-8 weeks  Transmission by intimate contact with saliva that contains virus during both primary infection and in repeated episodes of asymptomatic shedding. The initial site of virus replication → oropharyngeal epithelium→ progeny viruses infect B lymphocytes. The B-cell receptor for EBV is the complement component C3b receptor. During B-cell infection, only a limited number of early proteins are synthesized. Expression of these gene products results in latency and immortalization of the B cell.  The EBV genome is maintained as a circular plasmid-like form (episome) during latency. One protein that is expressed during latency is called EBNA1, and one of its key functions is to segregate the episomes into daughter cells following cell division.  Symptoms: fever, sore throat, lymphadenopathy, hepatitis; mild rash may be present EB Virus  Enveloped Complex DNA Virus: POXVIRIDAE  Poxviruses → large, genetically complex viruses having no obvious symmetry.  Agent of previous medical importance to humans, variola virus, was the cause of smallpox [(declared eradicated from the Earth):1) Availability of an effective, attenuated vaccine; 2) variola’s antigenic stability (that is, only a single antigenic type existed); 3) Absence of asymptomatic cases or persistent carriers; 4) Absence of an animal reservoir; and 5) Emotional effect of this highly lethal, disfiguring disease]  The highly effective poxvirus vaccine contains live vaccinia virus (causes cowpox), and the viral genome is currently being used in attempts to construct vectors carrying immunizing genes from other infectious agents.  The poxvirus, molluscum contagiosum virus (MCV), causes small, wartlike tumors (not to be confused with true warts caused by papilloma virus)  The genome is a single linear molecule of dsDNA, with a coding capacity for >> 200 polypeptides. The virion contains enzymes that are involved in early steps of replication. Humans are the natural host for variola and MCV, but monkeypox, cowpox, and several other animal poxviruses can also cause human disease.  MCV infection occurs only in humans, causing benign wartlike tumors on various body surfaces. Usually spread by direct contact, the virus can be spread among adults via sexual contact. Enveloped DNA Virus: HEPADNAVIRIDAE  HEPADNAVIRIDAE  The family Hepadnaviridae (hepatotropic DNA viruses) consists of hepatitis-causing viruses with DNA genomes  Each hepadnavirus has a narrow host range in which it produces both acute and chronic, persistent infections, but HBV is the only member of this family that infects humans  Because highly infectious virus is present in the blood of both symptomatic and asymptomatic patients, chronically infected individuals pose a serious threat to all healthcare workers, immunization of whom is generally required  A highly effective vaccine produced in genetically engineered yeast cells is available and included among routine childhood immunizations  Biologically, HBV is unique among human disease agents in that replication of the DNA genome proceeds via an RNA intermediate, which, in turn, is “reverse transcribed” by a viral enzyme homologous to the retrovirus reverse transcriptase  Retroviruses package an RNA genome, Hepadnaviridae package a DNA genome  Hepatitis B Virus  Structure and replication of hepatitis B virus ❖ The HBV virion, or “Dane particle,” consists of an icosahedral nucleocapsid enclosed in an envelope ❖ Organization of the genome: The short HBV DNA genome is unusual in that it is a partly single-stranded, partly double-stranded, non-covalently closed, circular DNA molecule (that is, one strand is longer than the other). ❖ Viral proteins: The four proteins encoded by viral DNA are: ❖ 1) The core protein [hepatitis B nucleocapsid core antigen (HBcAg)]; ❖ 2) Envelope protein [a glycoprotein referred to as hepatitis B surface antigen (HBsAg)]; ❖ 3) Multifunctional reverse transcriptase/DNA polymerase, which is complexed with the DNA genome within the capsid; and ❖ 4) A nonstructural regulatory protein designated the “X protein.”* Hepatitis B Virus Replication  Hepatitis B Virus: Transmission  Infectious HBV is present in all body fluids of an infected individual.  Sources of infection : blood, semen, saliva, and breastmilk  Incubation period is long, about 1- 6 months  The titer of infectious virus in the blood of an acutely infected patient can be as high as 108 virus particles/ but generally is lower in other body fluids.  Individuals infected at young age → chronic carriers, and an increased risk of developing hepatocellular carcinoma later in life.  Hepatitis B is primarily a disease of infants in developing nations, and mostly confined to adults through sexual intercourse or blood exposure from shared needles during injecting drug use.  HBV is important medically and in public health [acute liver disease + chronic, persistent infections ↔ death of infected individuals from cirrhosis and liver cancer]  Chronically infected people serve as the reservoir of transmissible virus in the population.  In most individuals, the primary infection is asymptomatic and resolves as a result of an effective cell-mediated immune response  Clinical significance: Acute Disease ❑ Phases in acute hepatitis B virus infections: long but variable incubation period of between 45 and 120 days. => pre-icteric (prejaundice) phase lasting several days to a week, characterized by mild fever, malaise, anorexia, myalgia, and nausea => acute, icteric phase and lasts for 1 to 2 months with dark urine[bilirubinuria], jaundice (a yellowish coloration of mucous membranes, conjunctivae, and skin) and an enlarged and tender liver. In 80 to 90 % of adults, a convalescent period of several more months is followed by complete recovery ❑ Monitoring the course of acute hepatitis B virus infection: Whereas liver-specific enzymes are important clinical determinants of all of the viral hepatitis, HBV infection is unusual in that the quantities of virions and virion components in the blood are so great that the time course of their appearance and clearance, along with that of the antibodies directed against them, serve as convenient markers of the stage of the disease and the likely future course. a. Appearance of viral antigens: During the incubation period, HBsAg and hepatitis B “e antigen” (HBeAg) are the first indicators of HBV infection to appear in the blood. Their presence indicates an active infection but does not distinguish between acute and chronic infections. Next, viral DNA, viral DNA polymerase, and complete virions become detectable. These continue to ↑ during the acute disease phase, when a patient’s blood has the highest titer of infectious virus. b. Appearance of antiviral antibodies: Antibodies to HBcAg rise concurrently with liver enzymes in the serum, whereas antiHBeAg antibodies and, still later, anti-HBsAg antibodies do not appear until the beginning of convalescence (generally after the respective antigens have disappeared from the blood. In those patients in whom the infection resolves completely, anti-HBcAg and anti-HBsAg antibodies remain present for life, providing immunity to reinfection. Continued presence of HBsAg beyond 6 months and absence of anti-HBsAg indicates that the infection has become chronic. A patient suffering chronic HBV infection is capable of eliciting an immune response against HBsAg but the anti-HBs antibody levels are too low to be detectable. All of the antibody that develops is complexed with circulating HBsAg.  Clinical Significance: Acute Disease 3. Fulminant hepatitis: In 1 to 2% of acute symptomatic cases, extensive necrosis of the liver occurs during the first 8 weeks of the acute illness. ✓ Accompanied by high fever; abdominal pain; and renal dysfunction, coma, and seizures. ✓ Fatal in roughly 8 % of cases.  Clinical significance: Chronic Disease  About 2 to 10 % of adults and over 25 % of young children remain chronically infected  The high rate of progression to chronic liver disease seen in infants born to HBV-infected mothers is thought to relate to the less competent immune status of newborns. Adults with immune deficiencies also (>>)normal immune systems). ❑ Types of chronic carriers: ✓ Asymptomatic carriers of HBsAg => have anti-HBeAg antibodies and little or no infectious virus in their blood. Later progression of liver damage or recurrence of acute episodes of hepatitis is rare in such patients. ✓ Have a higher risk of reactivation of disease, and a small fraction does progress to cirrhosis. ✓ Severe chronic hepatitis (“chronic active hepatitis”) results in more frequent exacerbations of acute symptoms, including progressive liver damage cirrhosis and/or hepatocellular carcinoma, chronic fatigue, anorexia, malaise, and anxiety. ✓ These symptoms are accompanied by active virus replication and the corresponding presence of HBeAg in the blood. ✓ Serum levels of liver enzymes and bilirubin are increased to varying degrees, reflecting the extent of necrosis. ✓ Life expectancy is significantly shorter in those individuals with cirrhosis. ❑ Development of hepatocellular carcinoma (hepatoma): HCC typically appears many years after the primary HBV infection, and the tumor itself is rather slow growing and only occasionally metastasizes. Clinically, a patient with HCC exhibits weight loss, right-upper-quadrant pain, fever, and intestinal bleeding. (DNA virus => mutations…)  Positive-stranded RNA Viruses 1) Replication in the cytoplasm; 2) Genomic RNAs serve as messenger RNAs and are infectious; 3) Genomic RNAs are non-segmented; 4) Virions do not contain any enzymes; and 5) Virus-specified proteins are synthesized as polyproteins that are processed by viral and cellular proteases, giving rise to individual viral proteins.  Some positive-strand RNA viruses are enveloped (Coronavirus), whereas others are not (Picornavirus)  A- PICORNAVIRIDAE  Picornaviruses → small, naked (non-enveloped), icosahedral  Contain a single-stranded, non-segmented RNA genome and four structural proteins  Divided into five genera: enteroviruses, rhinoviruses, cardioviruses, aphthoviruses, and hepatoviruses  Cardiovirus species cause encephalitis and myocarditis (mice)  Aphthovirus species→ “foot-and mouth” disease virus (cattle)  Enterovirus , Rhinovirus , and Hepatovirus → (humans)  The most intensively studied picornavirus is poliovirus (causative agent of poliomyelitis ↔ affects CNS (brain and spinal cord))  1- Enterovirus  Individuals are infected by ingestion of contaminated food or water  Stable at the low pH of the stomach, replicate in the GI tract, and are excreted in the stool  transmitted by the fecal-oral route  The virus can replicate in a variety of tissues. For ex, after replicating in the oropharynx and intestinal tract lymphoid tissue => enter the bloodstream and spread to various target organs (CNS)  The great majority of infections are asymptomatic  Infection, whether clinical or subclinical, usually results in protective immunity  No antiviral drugs are available for treatment of infections caused by Enterovirus species Coxsackieviruses  Clinical Significance All enteroviruses can cause CNS disease : acute aseptic meningitis syndrome,  any meningitis (infectious or noninfectious) / cause not clear after initial examination plus routine stains and cultures of the CSF Viral meningitis distinguished from bacterial meningitis : 1) The viral disease is milder; 2) ↑ of lymphocytes in the CSF, rather than the elevated neutrophils 3) The glucose concentration in the CSF is not ↓ Viral meningitis occurs mainly in the summer and fall (both children and adults) The treatment is symptomatic, and the course of the illness is usually benign Viruses can be isolated from the stool or from various target organs (CNS in meningitis cases and from conjunctival fluid in conjunctivitis cases) Evidence of infection can also be obtained by demonstration of a rise in antibody titer against a specific enterovirus  Poliovirus Infection  Poliomyelitis is an acute illness  the poliovirus selectively destroys the lower motor neurons of the spinal cord and brainstem  flaccid, asymmetric weakness or paralysis lower limbs Respiratory paralysis may also occur, following infection of the brainstem  Transmission : oro-fecal route, inhalation and conjunctiva  Incubation period: 4 days-4 weeks (average 10 d) 1- Asymptomatic infection: in 90 to 95 % of cases (no disease and sequelae); 2- Abortive infection; 3- Non-paralytic infection; or 4- Paralytic poliomyelitis  Post-poliomyelitis syndrome: 20 to 30 % of patients who partially or fully recover from paralytic poliomyelitis experience a new onset of muscle weakness, pain, atrophy, and fatigue 25 to 35 years after the acute illness Clinical outcomes of CNS invasion by poliovirus infection with poliovirus  Initially virus multiplies in epithelial cells of GIT & Lymphatic tissues, from the tonsils ⇓ Spreads to regional lymph nodes- enters bloodstream. ⇓ Carried to the spinal cord & brain. ⇓ In CNS, virus multiplies in neurons & destroys them and Degenerates the Nissl Bodies. ⇓ Lesions are mostly in anterior horn of spinal cord, cause paralysis.  2- Rhinoviruses  Rhinoviruses cause the common-cold syndrome  They differ in two important respects from enteroviruses: ❑ Whereas enteroviruses are acid stable (they must survive the acid environment of the stomach), rhinoviruses are acid labile ❑ Rhinoviruses, which replicate in the nasal passages, have an optimal temperature for replication < enteroviruses  rhinoviruses replicate efficiently at temperatures several degrees below body temperature  Rhinovirus replication is similar to that of the poliovirus  >100 serotypes of rhinoviruses  development of a vaccine is impractical  Studies have shown that, in addition to being spread by respiratory droplets, rhinoviruses can also be spread by hand-to-hand contact hand washing at appropriate intervals can be a useful preventive measure  3- Hepatoviruses  The sole member of this genus is hepatitis A virus (HAV)[or enterovirus 72]  Only one serotype and causes viral hepatitis  As with the enteroviruses, transmission is by the fecal-oral route, and the virus is shed in the feces  The main site of replication is the hepatocyte  severe cytopathology, and liver function is significantly impaired  In contrast to most other picornaviruses, HAV grows poorly in tissue culture  The prognosis is generally favorable, and the development of persistent infection and chronic hepatitis is uncommon  Prevention depends on taking measures to avoid fecal contamination of food and water  Immune globulin has been used for many years, mainly as post-exposure prophylaxis.  Hepatitis A: RNA virus Replication in hepatocytes (few in enterocytes) Oro-fecal transmission Incubation: 2-6 wks IgG Anti-HAV→ immunity Fulminant liver failure → rare (0.1%) Vaccine ++ Hepatitis A: Clinical Features  B- Caliciviridae  Caliciviruses are small, non-enveloped, spherical particles  Each contains a single-stranded, non-segmented RNA genome, and a single species of capsid protein  Norovirus is the prototype human calicivirus  There are at least four strains of human caliciviruses and are a major cause of gastroenteritis  1- Caliciviruses  Norovirus (Norwalk-like virus) replicates in the GI tract and is shed in the stool.  Infection is by the fecal-oral route, following ingestion of contaminated foods or water, by person-to-person contact, or by contact with contaminated surfaces  Norovirus is a major cause of epidemic acute gastroenteritis, particularly at schools, camps, military bases, prisons, and other closed environments such as cruise ships  It affects primarily adults and school-age children but not infants  The clinical presentation is characterized by nausea, vomiting, and diarrhea. Symptoms last 24 to 48 hours, and the disease is self-limited  Radioimmunoassays and ELISA (Enzyme-Linked Immunosorbent Assay) tests → for the detection of antiviral antibodies  No specific antiviral treatment is available  Careful attention to hand washing and measures to prevent contamination of food and water supplies should reduce the incidence of these infections  2- Hepatitis E Virus (HEV)  HEV is a non-enveloped, single-stranded RNA virus  Major cause of enterically transmitted, waterborne hepatitis  The peak incidence is in young adults, and the disease is especially severe in pregnant women, in whom death can result from HEV infection  Viral RNA can be detected in the feces of infected individuals by RT-PCR and nearly all serologically confirmed epidemics of HEV can be attributed to fecally contaminated water  Apart from epidemic situations, the diagnosis of HEV cannot be made in an infected individual solely on clinical grounds. However, specific tests are available to detect antibodies to HEV  As with hepatitis A, progression to chronic hepatitis is not seen  Neither antiviral treatment nor vaccine is currently available  C- Togaviridae  Enveloped, icosahedral viruses that contain a positive-sense, single- stranded RNA genome and 3 structural proteins  The capsid (C) protein encloses the viral RNA, forming the nucleocapsid, and the 2 other proteins (E1 & E2) are glycoproteins that form the hemagglutinin-containing viral spikes that project from the lipid bilayer  Classification  The family Togaviridae is divided into 2 genera ❖ Alphavirus ❖ Rubivirus  1- Alphavirus  Arthropod-borne viruses (arboviruses)  Transmitted to humans and domestic animals by mosquitoes.  All alphaviruses share a common group antigen. Some arboviruses were initially isolated from horses, hence, the word “equine” in their names  Alphaviruses have a broad host range, being able to replicate in organisms that are widely separated phylogenetically, such as mosquitoes and humans. Following inoculation of an Alphavirus by a mosquito, the patient is observed to have a viremia, following which the virus may be seeded in various target organs (the CNS in the encephalitis viruses).  Several different clinical syndromes are associated with Alphavirus infections of humans: 1) Acute encephalitis (Eastern and Western equine encephalitis viruses), 2) Acute arthropathy (Chikungunya virus), and 3) A febrile illness with a flulike syndrome (Venezuelan equine encephalitis virus).  The majority of infections are subclinical and can be diagnosed only by the demonstration of an immune response.  The most important measure for prevention of infections caused by Alphavirusis control of the mosquito vector population. A Venezuelan equine encephalitis vaccine is available.  2- Rubivirus  The structure and replication of rubella virus are basically = the alphaviruses  Respiratory secretions of an infected person are the primary vehicles for rubella virus transmission [ NOT Arthropod-borne]  Rubella causes a mild clinical syndrome ↔ generalized maculopapular rash and occipital lymphadenopathy*[“German measles,” not to be confused with “measles” (rubeola), caused by the measles virus ]  The incubation period of Rubella virus is 9-11 days  The clinical significance of rubella lies not in the primary infection* but, rather, in the severe damage possible to the developing fetus (especially in the first trimester) when a woman is infected during pregnancy (congenital rubella)  Congenital heart disease; cataracts; hepatitis; and abnormalities related to the CNS (mental retardation, motor dysfunction, and deafness)  Fetal damage is preventable by use of the live attenuated rubella vaccine that is included with the routine childhood vaccinations (not given to women who are already pregnant or to immunocompromised patients, including babies) Clinical Features of Rubella (German Measles)  The disease occurs principally in children but may affect all ages  Two types – Congenital or Post-Natal ⇒ If rubella occurs in early pregnancy, the fetus may die. Transient effects observed in infants with Congenital Rubella infection includes : Cardiac defects Cataract Deafness Hepatosplenomegaly Thrombocytopenic purpura Myocarditis Bone lesions Mental retardation ⇒ In NN and Adults, infection occurs through the mucosa of the upper respiratory tract and termed as post-natal rubella infection: Begins with malaise followed by fever, lymphadenopathy, and rashes; arthritis is more common in females  The infection of Rubella is acquired by inhalation ⇓ The replication of virus occurs in Cervical lymph nodes ⇓ Viremia occurs and can be demonstrated As early as the 7th day before the rash ⇓ After about 7 days of viremia, the rashes develop, First on the face and then spreading to neck, trunk and extremities sparing palms & soles  D- Flaviviridae  The members of this family are enveloped viruses that contain a single stranded RNA genome and three structural proteins. [ FLAVI= YELLOW ]  The capsid (C) protein and the viral RNA form the icosahedral nucleocapsid, and the other two proteins are envelope-associated.  3 genera: Flavivirus , Hepatitis C virus, and Pestivirus (classical swine fever virus and bovine viral diarrhea virus→ veterinary interest)  1- Flaviviruses  More than sixty viruses. These include many viruses of medical importance, such as yellow fever, St. Louis encephalitis, Japanese encephalitis, dengue fever viruses, and West Nile virus, all of which are mosquito transmitted  Tickborne encephalitis virus is transmitted by ticks. [Like the viruses in the Alphavirus genus of the family Togaviridae , most of the viruses in this genus are arboviruses]  Transmission to humans by the bite of an infected mosquito or tick  These viruses are maintained in nature by replicating alternately in an arthropod vector and a vertebrate host  Clinical Significance  Flavivirus are associated with several different clinical syndromes ✓ Encephalitis (St. Louis encephalitis, Japanese encephalitis, and tickborne encephalitis viruses); ✓ Hemorrhagic fever (yellow fever virus); and ✓ Fever, myalgia, and rash (dengue viruses)  Little mortality associated with classic dengue fever  A severe form of dengue infection occurs, particularly in infants and young children  dengue hemorrhagic fever or dengue shock syndrome associated with a significant mortality (10 % or higher) if untreated  Like dengue fever, West Nile fever is a mosquito-transmitted, acute, usually self- limited illness that presents chiefly with fever, malaise, lymphadenopathy, and rash  Infection may also result in aseptic meningitis or meningoencephalitis, especially in older adults  2- Hepatitis C Viruses  Hepatitis C viruses (HCV) are heterogeneous and can be divided into six types on the basis of their nucleotide sequences.  Major cause of post-transfusion hepatitis, IV drug users , hemodialysis and tattooing  There is evidence for sexual transmission as well as for transmission from mother to infant  In the infected individual, viral replication occurs in the hepatocyte and in mononuclear cells (lymphocytes and macrophages)  Destruction of liver cells may result both from a direct effect of the activities of viral gene products and from the host immune response, including cytotoxic T cells  Although DNA viruses are associated with chronic infection and cancer development, this is not generally the case for RNA viruses  Certain strains of HCV have been associated with hepatocellular carcinoma , even in the absence of cirrhosis and also interferon-γ (IFN-γ) treatment failures  The majority of infections are subclinical, but about 25% present with acute hepatitis, including jaundice. More importantly, a significant proportion of infections progress to chronic hepatitis and cirrhosis [some of these individuals develop hepatocellular carcinoma] 2- Hepatitis C Viruses  Acute and chronic hepatitis C virus (HCV) infection can affect the liver as well as nonhepatic tissues, including the skin  Mixed cryoglobulinemia, porphyria cutanea tarda, lichen planus, and necrolytic acral erythema are the cutaneous diseases most commonly associated with HCV infection, but other skin conditions and symptoms have been associated with HCV, such as psoriasis or pruritus  In some cases, cutaneous manifestations may be the first indication of HCV and should prompt HCV testing  In most cases, skin manifestations disappear after appropriate HCV treatment or viral clearance  D- Coronaviridae  Coronaviruses are large, enveloped, pleomorphic particles, with a distinctive arrangement of spikes (peplomers) projecting from their surfaces. [Note: These projections have the appearance of a solar corona, which gives the virus its name.]  The Coronavirus genome is the largest described for any RNA virus thus far. Human coronaviruses have been most commonly implicated in upper respiratory infections, causing 10 to 30 % of cases of the common cold Characteristics of Human Hepatitis Viruses  Retroviridae or RNA Tumor Viruses  Includes a large number of disease-producing animal viruses, several of which are of clinical importance to humans  Retroviridae are distinguished from all other RNA viruses by the presence of an unusual enzyme, reverse transcriptase, which converts a single-stranded RNA viral genome into double-stranded viral DNA  These viruses reverse the order of information transfer (RNA serving as a template for DNA synthesis, rather than DNA serving almost universally as a template for RNA synthesis), => termed retroviruses  Retroviridae contain two genera that are of human interest: ✓ Lentivirus** → Human Immunodeficiency Viruses 1 and 2 (HIV-1 and -2) responsible for many immunological and neurological diseases without oncogenic properties (HTLV-BLV group) ✓ The Human T-cell Lymphotropic Virus-Bovine Leukemia Virus group (HTLV-BLV group), → Human T-cell Lymphotropic Viruses 1 and 2 (HTLV-1 and -2) 1- Retroviruses  1- Retrovirus: Structure  The viral envelope, formed from the host cell membrane, contains a complex HIV protein and appears as spiked knobs. The full-length protein, called gp160, is cleaved into two peptides by a viral protease ["gp" indicates that the protein is glycosylated]  transmembrane protein called gp41, or TM, whereas the surface exposed portion of the protein is called gp120, or SU  Host cell proteins, including the MHC* class II proteins, are also found (envelope)  The virion has a cone-shaped, icosahedral core containing the major capsid protein (p24 or CA)  Between the capsid and the envelope is an outer matrix protein (p17or MA), which directs entry of the double-stranded DNA provirus into the nucleus (essential for the process of virus assembly)  There are 2 identical copies of the positive-sense, ss RNA genome in the capsid (unlike other viruses, retroviruses are diploid)  The RNA is tightly complexed with a basic protein (p7 or NC) in a nucleocapsid structure that differs in morphology among the different retrovirus genera  Also within the capsid → the enzymes reverse transcriptase and integrase (for viral DNA synthesis and integration into the host cell chromosome) and protease (virus maturation) Life Cycle of Retroviruses  Human Immunodeficiency Virus (HIV)  The HIV RNA genome contains three major genes: gag , pol and env  The gag gene encodes p17 (MA), p24 (CA), and p7 (NC) (core and matrix proteins) (gag=group specific antigen=makes the cone shape viral capsid)  The pol gene encodes reverse transcriptase, protease, integrase, and ribonuclease (pol=polymerase)  The env gene encodes gp41 (TM) and gp120 (SU) (transmembrane and surface proteins) (env=envelope: makes surface protein (gp120) and trans mb protein (gp41) enable virus to fuse CD4)  Transmission of HIV  There has been no firm evidence for transmission by saliva, urine, nonsexual contact in which blood is not exchanged, or by an insect bite. 1. Sexual contact: HIV, present in both semen and vaginal secretions, is transmitted primarily as cell-associated virus in the course of either homosexual or heterosexual contact. Disruption of mucosal surfaces by sexually transmitted diseases, particularly those such as syphilis and chancroid that result in genital ulcerations, may greatly facilitate HIV-1 infection. The non-ulcerative sexually transmitted pathogens have also been documented to enhance HIV transmission, at least in part due to replicative synergy between the viral and bacterial pathogens. 2. Transfusions: HIV has been transmitted by transfusion with whole blood, plasma, clotting factors, and cellular fractions of blood. 3. Contaminated needles: Transmission can occur by inoculation with HIV-contaminated needles or syringes among drug users or accidentally if a contaminated needle punctures the skin of a health care worker. 4. Perinatal transmission: An HIV-infected woman has a 15 to 40 % chance of transmitting the infection to her newborn, either transplacentally, during passage of the baby through the birth canal, or via breastfeeding Steps of HIV Replication  VIRAL REPLICATION HIV  Pathogenesis  The pathology of HIV disease results from either tissue destruction by the virus itself or the host’s response to virus-infected cells.  HIV can induce an immunodeficient state that leads to opportunistic diseases* (rare in the absence of HIV infection).  The progression from HIV infection to AIDS develops in 50 % of HIV-infected individuals in an average of 10 years, and, if untreated, it is uniformly fatal, generally within 2 years of diagnosis [significant fraction (about 10 %) of HIV infected individuals who have not developed AIDS after 20 years].  Development from HIV infection to end-stage AIDS progresses through several phases: 1. Initial infection: After the acquisition of HIV, the initially infected cells are generally macrophages within the genital tract → HIV disseminates via the blood, and virus may then localize in dendritic cells throughout the lymphoid tissue → CD4+ lymphocytes moving through the germinal centers of lymph nodes  reservoir of chronically HIV infected cells within the lymphatic tissue throughout the body. 2. Acute phase viremia: Several weeks after the initial infection with HIV, one-third to two-thirds of individuals experience an acute disease syndrome (primary infection) similar to infectious mononucleosis. → high level of virus replication occurring in CD4+ cells. Large amounts of virus and capsid protein (CA antigen) are present in the blood, but circulating antibody does not appear until 1 to 10 weeks after the initial infection (seroconversion). During this window of time, antibody tests will not identify HIV-infected people. Lymph nodes also become infected during this time and later serve as the sites of virus persistence during the asymptomatic period.  Pathogenesis 3. Latent period: The acute phase viremia is eventually reduced significantly with the appearance of a HIV- specific cytotoxic T-lymphocyte response, followed by a humoral antibody response. A clinically asymptomatic or “latent” period lasting from months to many years follows the acute infection => the majority (90 %) of HIV proviruses are transcriptionally silent, so that only 10 % of the cells containing integrated HIV DNA also contain viral mRNA or viral proteins. There is continuous loss of those CD4+ cells in which HIV is replicating, active replacement through stem cell multiplication compensates for this loss, and the CD4+ count declines only slowly over a period of years. In addition, the host immune response is still sufficiently effective to maintain a relatively stable, low level of virus production. Virus isolated during this period replicates more slowly than does virus isolated later during symptomatic AIDS. The infection remains relatively clinically asymptomatic as long as the immune system is functional (patients with a higher viral load progress more rapidly to symptomatic AIDS and death). 4. Clinical complications of HIV infection during the latent period: lasting on average about 10 years → multiple, nonspecific conditions/ persistent, generalized lymphadenopathy (swollen lymph nodes); diarrhea; chronic fevers; night sweats; and weight loss. Common opportunistic infections/ herpes zoster and candidiasis, may occur repeatedly during this period as well as when patients progress to AIDS. 5. Progression to AIDS: The progression from asymptomatic infection to AIDS is not sudden but, in fact, occurs as a continuum of clinical states. A number of virologic and immunologic changes occur that affect the rate of this progression. Any stimulation of an immune response causing activation of resting T cells activates HIV replication. Not only does this increase the number of infected CD4+ cells, but it also increases the opportunity to create generations of virus mutants*. With the CD4+ count falling below 200/μl and the appearance of increasingly frequent and serious diseases and opportunistic infections (“AIDS defining illnesses”), the patient is said to have AIDS.  Pathogenesis and Clinical Significance 6. End-stage AIDS: either by HIV itself or by opportunistic organisms. The weakening immune system leads to many complications, including malignancies. a. Spread of HIV to additional body sites: Cell types other than CD4+ lymphocytes can be infected by HIV→ infected cells of the monocyte-macrophage lineage(not killed as rapidly as CD4+ T cells) → transport the virus into other organs (microglia in brains of patients with AIDS encephalopathy resulting in severe dementia): unrelated to CD4+ depletion but an expanded tropism of variant HIV. HIV infection of blood cell progenitors in the bone marrow => anemia b. Opportunistic infections in AIDS: recurrent infections with fungi, bacteria, and viruses occur as the CD4+ cell count declines : nervous system → Toxoplasma , Cryptococcus , mycobacteria. The eye can be infected with HIV, but also with CMV  retinal destruction. The lungs → P. jirovecci pneumonia , Mycobacterial infections (tuberculosis ). Serious GI tract illnesses → CMV colitis, protozoal parasitic diseases, infections with G- enteric bacteria. The immune deficiency also provides the opportunity for latent infections to recur repeatedly or to become chronic and spread extensively → EBV, VZV, human papillomavirus, and HSV. Mucocutaneous candidiasis (oral, esophageal, or vaginal) are common c. Malignancies associated with AIDS: KS, which involves skin, mucous membranes, and deep viscera. Various lymphomas, including those of the CNS, are also common Maraviroc Enfuvirtide HIV Life Cycle Zidovudine Didanosine Stavudine Lamivudine Saquinavir Indinavir Ritonavir  2- Human T-cell Lymphotropic Viruses (-1 and -2)  Human T-cell lymphotropic viruses, types 1 and 2 (HTLV-1 and -2) are genetically and biologically similar. HTLV-1 has definitively been associated with a human malignant disease, Adult T-cell Leukemia (ATL), and a less common neurologic condition, HTLV- associated myelopathy/tropical spastic paraparesis (HAM/TSP). There are six subclasses of HTLV-1, each of which is endemic to different regions of the world. No conclusive evidence links HTLV-2 to any known disease. A. Transmission of HTLV ✓ In highly endemic regions, mother to fetus or newborn is the most common mode of transmission. This is accomplished via infected lymphocytes either transplacentally or in breast milk. ✓ Infection can be transmitted sexually by infected lymphocytes contained in semen. ✓ Any blood products containing intact cells are also a potential source of infection.  Tax Protein: - Activates transcription factors - Suppresses transcriptional inhibitors - Suppresses cell-cycle inhibitors 2- Human T-cell Lymphotropic Viruses (-1 and -2) B. Pathogenesis and clinical significance of adult T-cell leukemia Both HTLV-1 and HTLV-2 infect lymphocytes: HTLV-1 has a tropism for CD4 lymphocytes, whereas HTLV-2 preferentially infects CD8 lymphocytes. Following infection, the virus becomes integrated in the host cell as a provirus and transforms a polyclonal population of T cells*. Continued multiplication of T lymphocytes over a period of many years  accumulation of many chromosomal aberrations. The majority of infected individuals are asymptomatic. ATL typically appears 20 to 30 years after initial infection, when an increasingly larger population of monoclonal malignant ATL cells develops, and infiltration of various visceral organs by these cells occurs  serum chemistry abnormalities, and impairment of the immune system → opportunistic infections. Median survival after appearance of acute ATL is about 6 months. C. Pathogenesis and clinical significance of HTLV-associated myelopathy/tropical spastic paraparesis About 1 to 2% of HTLV-1–infected individuals develop HAM/TSP. It usually appears only a few years after infection. CNS involvement is indicated by: 1) the presence of anti-HTLV-1 antibody in the CSF, 2) lymphocytic infiltration and demyelination of the thoracic spinal cord, and 3) brain lesions. The lymphocyte count is normal. Characterized by progressive spasticity and weakness of the extremities, urinary and fecal incontinence, hyperreflexia, and some peripheral sensory loss. D. Other manifestions of HTLV-1 infection: Uveitis and retinal vasculitis. In addition, a chronic, severe form of infectious dermatitis can also result  Negative-Strand RNA Viruses  All are enveloped  Virions contain an RNA-dependent RNA transcriptase that synthesizes viral mRNAs using the genomic negative-strand RNA as a template  The genomic negative-strand viral RNAs are not infectious, in contrast to the genomic RNAs of positive-strand viruses  Following entry and penetration, the first step in the replication is the synthesis of mRNAs, whereas with positive-strand RNA viruses, the first step in replication is translation of the incoming genomic RNA  Some negative-strand RNA viruses have segmented genomes, whereas others have non-segmented genomes  Most of these viruses replicate in the cytosol, the replication of influenza virus RNA (orthomyxovirus) occurs in the nucleus  A- Rhabdoviridae  Rhabdoviruses are enveloped, bullet-shaped viruses. Each contains a helical nucleocapsid  The viruses in the family Rhabdoviridae known to infect mammals ; divided into two genera: ▪ Lyssavirus (rabies virus, the rhabdovirus of greatest medical importance to humans) ▪ Vesiculovirus [vesicular stomatitis virus (VSV), a virus of horses and cattle]  Humans are usually infected by the bite of an animal  The extremely variable incubation period depends on the host’s resistance, amount of virus transferred, and distance of the site of initial infection from the CNS  Incubation generally lasts 1 to 8 weeks but may range up to several months or, in unusual cases, as long as several years following exposure.  Clinical illness may begin with an abnormal sensation at the site of the bite, then progress to a fatal encephalitis, with neuronal degeneration of the brain and spinal cord.  Symptoms include hallucinations; seizures; weakness; mental dysfunction; paralysis; coma; and, finally, death  Following inoculation, the virus may replicate locally, but then enters the peripheral nervous system, where it passively travels to the CNS. The virus next infects the brainstem, cerebellum, and other brain structures (diffuse encephalitis) From the brain, the rabies virus can travel along autonomic nerves, leading to infection of other tissues, including the skin, cornea, and salivary glands  B- Paramyxoviridae  Paramyxovirinae, includes three genera: 1) Paramyxovirus (parainfluenza viruses→ URT infections); 2) Rubulavirus (mumps virus); 3) Morbillivirus (measles virus)  Pneumovirinae → respiratory syncytial virus (RCV) [respiratory tract pathogen in the pediatric population], and human metapneumovirus (hMPV).  Paramyxoviruses are spherical, enveloped particles that contain a non-segmented, negative-strand RNA genome → helical nucleocapsid surrounded by an envelope that contains two types of integral membrane or envelope proteins : ❑ HN protein (H → hemagglutinin and N → neuraminidase) involved in the binding of the virus to a cell [Measles virus lacks the neuraminidase activity] ❑ F protein (F → for fusion), functions to fuse viral and cellular membranes=> facilitating virus entry into the cytoplasm, where viral replication occurs.  Paramyxovirus mRNA transcription, genome replication, and viral assembly and release resemble those of the rhabdoviruses B- Paramyxoviridae Mumps Virus  1- Paramyxovirus  The clinically important viruses in this genus are types 1 and 3 human parainfluenza viruses (hPIV)  They cause croup, pneumonia, and bronchiolitis, mainly in infants and children  “Parainfluenza”  influenza-like symptoms, and, like influenza virus, these viruses have both hemagglutinating and neuraminidase activities(=> “para”)  2- Rubulavirus  This genus contains hPIV types 2 and 4 and mumps virus  Types 2 and 4 human parainfluenza viruses: similar to those of types 1 and 3 viruses. Type 4 hPIV has been associated only with a mild URT illness (children and adults)  Mumps virus: acquired childhood infections (rarely adults) ❑ The virus spreads by respiratory droplets ❑ 1/3 → subclinical ❑ Clinical presentation and diagnosis → infection and swelling of the salivary glands, (primarily the parotid glands) ❑ Also the pancreas, CNS, and testes  Orchitis (inflammation of the testis)  sterility ❑ Live, attenuated vaccine [Individuals who have had the disease develop lifelong immunity] Mumps Time Course  3- Morbillivirus  Measles virus is the only → humans. Other in the genus Morbillivirus → animals 1. Viral replication: The cellular receptor for measles virus is the CD46* molecule. The viral attachment protein has hemagglutinating activity, it lacks neuraminidase activityH protein, rather than HN protein. An F protein facilitates uptake of the virion. Measles virus replication is characterized by the formation of giant multinucleate cells (syncytium formation), resulting from the action of the viral spike F protein. 2. Pathology: transmitted by sneeze- or cough-produced respiratory droplets o The virus is extremely infectious o Replicates initially in the respiratory epithelium → lymphoid organs o Measles ( or rubeola) begins with a prodromal period of fever, Cough, Coryza (runny nose), and Conjunctivitis (3 C"s) o 2-3 d later→ Koplik spots (small white spots on bright red mucous membranes of the mouth and throat) followed by a generalized macular rash, beginning at the head and traveling slowly to the lower extremities (after the rash appears, the patient is no longer infectious) o The major morbidity and mortality caused by measles are associated with various complications of infection, especially those affecting the lower respiratory tract and the CNS.  post-infectious encephalomyelitis** (1 of 1,000 cases usually occurring within 2 weeks after the onset of the rash) o Children are particularly susceptible, especially those weakened by other diseases or malnutrition KOPLIK  Measles Time Course  4- Pneumovirus  RSV is the major viral respiratory tract pathogen in the pediatric population and the most important cause of bronchiolitis in infants; pneumonia in young children, an influenza-like syndrome in adults, and severe bronchitis with pneumonia in older adults and organ transplant recipients ❑ RSV has one envelope protein that functions as an attachment protein and another that functions as a fusion protein, but, like measles virus, RSV lacks neuraminidase activity. ❑ RSV is transmitted by respiratory droplets or by contaminated hands carrying the virus to the nose or mouth. Repeated infections are common  hMPV is the second leading cause of bronchiolitis in infants but can also cause pneumonia and croup in children  C- Orthomyxoviridae  Spherical, enveloped viruses containing a segmented, negative strand RNA genome  Two types of spikes : H protein and N protein [in contrast to the paramyxoviruses, in which H and N activities reside in the same spike protein.] Both the H and N influenza proteins are integral membrane proteins.  The M (matrix) proteins underlie the viral lipid membrane. The RNA genome, located in a helical nucleocapsid, is composed of 8 distinct segments of RNA, each of which encodes one or more viral proteins. Each nucleocapsid segment contains not only the viral RNA but also four proteins (NP, the major nucleocapsid protein, and three P (polymerase) proteins that are present in much smaller amounts than NP and are involved in synthesis and replication of viral RNA)  Infect humans, horses, and pigs, as well as nondomestic waterfowl, and are the cause of influenza.  Divided into 3 types: Influenzae A, B, and C. Only influenza virus types A and B are of medical importance.  Type A influenza viruses differ from type B viruses in that they have an animal reservoir TYPE A undergoes antigenic shift and drift TYPE B undergoes antigenic drift only TYPE C is relatively stable Epidemics of Influenza A and B arise due to minor Ag drifts as a result of mutation Pandemics due to Ag shift a virus with a new H subtype emerges => the population has no immunity against the new strain ( 3 Ag shifts occurred in the 20th century) Neuraminidase → enzyme which hydrolyses sialic acid ↔ assisting in the release of viral particles. Haemagglutinin → enables the virus to attach to host cells by binding to epithelial sialic acid residues. It also helps in the fusion of the viral envelope with the cell membrane  Viral Replication  2 unusual features distinguish the influenza viruses from the other RNA viruses  First, the synthesis of influenza virus mRNAs and the replication of the viral genome occur in the nucleus*  Second, compounds such as actinomycin D and α-amanitin, which inhibit mRNA transcription by eukaryotic RNA polymerase II (Pol II), also inhibit the replication of influenza virus 1. Viral entry into the cell: Influenza virus attaches to sialic acid residues on host cell glycoproteins or glycolipids => Entry via receptor-mediated endocytosis. Both the attachment and the fusion functions are associated with the H protein. 2. Synthesis and translation of viral mRNAs: The nucleocapsid segments are released into the cytosol, and, as with the other negative-strand RNA viruses, the viral genomic RNA serves as the template for synthesis of viral mRNAs. Each of the eight genome segments directs the synthesis of one positive-strand mRNA. However, influenza virus is distinguished from the other negative strand viruses in that, although the virions contain proteins that can transcribe mRNAs, these enzymes lack the ability to cap and methylate viral mRNAs  synthesis begins with “cap snatching,” in which the viral P proteins cleave 5'-terminal sequences from nascent host cellular Pol II transcripts (previously synthesized, capped, and methylated in the nucleus). The oligonucleotide fragments are then used as primers for the synthesis of the viral mRNAs 3. Assembly and release : Once the viral mRNAs are made and translated, the NP and the three P proteins move into the nucleus => replication of the eight genomic segments begins, and progeny nucleocapsids are assembled. Meanwhile, certain regions of the plasma membrane are virus modified by insertion of H and N proteins and alignment of the M protein on the inner side of the plasma membrane. The nucleocapsids move from the nucleus to the cytosol and, finally, to virus-modified regions of the plasma membrane  giving rise to extracellular viral particles. Viral release is facilitated by the N protein, which cleaves neuraminic acid on the cell surface Replication Cycle of Influenza Virus  Pathology and Clinical Significance  In humans, influenza is spread by respiratory droplets and is an infection solely of the respiratory tract (rarely viremia or spread to other organ systems) (SEASONAL DISEASE)  Influenza has an acute onset, with symptoms including a nonproductive cough and chills, followed by high fever, muscle aches (caused by circulating cytokines), and extreme drowsiness  Runny nose is unusual, differentiating influenza virus infection from the common cold.  The disease runs its course in 4 to 5 days, after which recovery is gradual  The most serious problems/pneumonia, occur in the very young, older adults, and people with chronic cardiac or pulmonary disease or those who are immunodeficient  Reye syndrome is a rare and serious complication of viral infections in children, especially in those who have had chickenpox or influenza B (Aspirin, used to lower virus-induced fever, contributes to the appearance of this syndrome)  TIME COURSE OF INFLUENZA (Incubation period= 1-2 days)  Complications: bacterial pneumonia=> Influenza can damage the lining of the respiratory tract and bacteria establish an infection (S.pneumonia and S.aureus are the common causes) NB: Pneumonia caused by the virus itself is less common  Influenza Virus Immunology  When individuals are infected with influenza virus, antibodies are made against the various viral proteins (against the H protein that are neutralizing and the best index of protection)  The antigenic properties of the influenza virus proteins are important (basis for the classification of influenza) 1. Types and subtypes: Influenza viruses are classified as types A, B, and C, depending on their inner proteins, mainly the M and NP proteins. T