HERPESVIRUSES.pptx

HERPESVIRUSES BY DR GBOLAGADE ADEWUYI HERPESVIRUSES 'Herpein' - 'to creep' = (refering to spreading cutaneous lesions, usually involving blisters, seen in flares of HSV 1 & 2 and herpes zoster (shingles) chronic/latent/recurrent infections HERPES VIRUS TYPES THAT INFECT HUMANS Herpes simplex vir...

HERPESVIRUSES BY DR GBOLAGADE ADEWUYI HERPESVIRUSES 'Herpein' - 'to creep' = (refering to spreading cutaneous lesions, usually involving blisters, seen in flares of HSV 1 & 2 and herpes zoster (shingles) chronic/latent/recurrent infections HERPES VIRUS TYPES THAT INFECT HUMANS Herpes simplex virus Type 1 (HSV-1) Herpes simplex virus Type 2 (HSV-2) Epstein Barr virus (EBV) Cytomegalovirus (CMV) Varicella Zoster Virus (VZV) Human herpes virus 6 (exanthum subitum or roseola infantum) • Human herpes virus 8 (Kaposi's sarcoma associated herpes virus) • Herpes B virus of monkeys can also infect humans. • • • • • • HERPESVIRUSES • Capacity to persist in host indefinitely in nucleus of the cell • Every vertebrate species has at least one host specific herpesvirus • Varicella zoster and herpes simplex viruses establish latent infections in neurons ↓ reactivation • Some are cancer causing Herpesvirus Virion Spherical 150- 250 nm Icosahedral Enveloped ds DNA linear 124-235 kbp More than 35 proteins in virion Envelope: 8nm spikes viral glycoproteins. Fc receptors. • Replication - nuclear, bud from nuclear membrane • Infection: Lytic, latent and recurrent • • • • Herpes virion -Properties • Size:150-200nm • Envelope: Present; associated glycoproteinsspikes. • Tegument: Protein-filled region between capsid and envelope. • Capsid: Icosahedral, 95-105nm diameter; 162 hexagonal capsomers. • Core: Toroidal (DNA around protein), ~75nm diameter. • Genome: Large, 130-230kbp and encode at least 100 different proteins and many virus-specific enzymes , Linear, d/s DNA,, G+C 31-75 % CHARACTERISTICS OF HERPES VIRUSES • Herpesviruses have large, enveloped icosadeltahedral capsids containing double-stranded DNA genomes. • Herpesviruses encode many proteins that manipulate the host cell and immune response. • Herpesviruses encode enzymes (DNA polymerase) that promote viral DNA replication and are good targets for antiviral drugs. • DNA replication and capsid assembly occurs in the nucleus. • Virus is released by exocytosis, cell lysis, and through cell-to-cell bridges. CHARACTERISTICS OF HERPES VIRUSES • Herpesviruses can cause lytic, persistent, latent, and (for Epstein-Barr virus) immortalizing infections. • Herpesviruses are ubiquitous. • Cell-mediated immunity is required for control. • The members in the sub-family alpha have a cytopathic effect on cells, which become multinucleated giant syncytial cells with intranuclear Inclusion bodies. CHARACTERISTICS OF HERPES VIRUSES Latency • During the primary infection the viruses migrate up the nerves to the sensory ganglia and reside there. • The viruses rest there until reactivation occurs through some stress, such as – menstruation, anxiety states, fever, sunlight exposure, – and weakening of the cell-mediated immune system, as with AIDS or chronic disease. • The viruses then migrate out to the peripheral skin via the nerves to cause local destruction. CHARACTERISTICS OF HERPES VIRUSES Cytopathic effect • The herpesviridae that cause cell destruction are the alpha sub group viruses (herpes simplex virus 1 and 2, and varicella-zoster). • This cell destruction results in the separation of the epithelium and causes blisters (vesicles). • Microscopic study of skin biopsies or scrapings from blister bases in herpes simplex, chickenpox, and zoster all reveal multinucleated giant cells and intranuclear inclusion bodies. • Viral proteins are inserted into the host cell plasma membranes, resulting in cell fusion to form multinucleated giant cells. • Intranuclear inclusions are considered to be areas of viral assembly. CHARACTERISTICS OF HERPES VIRUSES • Both CMV (beta subgroup) and EpsteinBarr virus (gamma subgroup) have less cytopathic effects. • Patients with compromised cell-mediated immune status are more likely to suffer from severe herpesviridae infections such as disseminated HSVor multi-dermatomal zoster. • CMV frequently causes disease in AIDS patients. CHARACTERISTICS OF HERPES VIRUSES MORPHOLOGY • All Herpesviruses are structurally similar. Each has an icosahedral core surrounded by a lipoprotein envelope. • The genome is linear double-stranded DNA, but they differ in size and gene orientation. • The virion does not contain a polymerase. • They are (120-200nm in diameter), second in size only to poxviruses. • They replicate in the nucleus, form intranuclear inclusions, and are the only viruses that obtained their envelope by budding from the nuclear membrane. • The virions of Herpesviruses possess a tegument located between the nucleocapsid and the envelope. This structure contains regulatory proteins, such as transcription and translation factors, which play a role in viral replication. Herpesvirus Particle • All herpesviruses – identical morphology • Cannot be distinguished from each other under electron microscopy. SUBFAMILY Classification of Human Herpesviruses VIRUS PRIMARY TARGET CELL SITE OF LATENCY MEANS OF SPREAD Close contact (sexually transmitted disease) Close contact (sexually transmitted disease) Respiratory and close contact Alphaherpesvirinae Human herpesvirus 1 Herpes simplex type 1 Mucoepithelial cells Neuron Human herpesvirus 2 Herpes simplex type 2 Mucoepithelial cells Neuron Human herpesvirus 3 Varicella-zoster virus Mucoepithelial and T cells Neuron Gammaherpesvirinae Human herpesvirus 4 Epstein-Barr virus B cells and epithelial cells B cell Saliva (kissing disease) Human herpesvirus 8 Kaposi sarcomarelated virus Lymphocyte and other cells B cell Close contact (sexual), saliva? Betaherpesvirinae Human herpesvirus 5 Cytomegalovirus Monocyte, granulocyte, lymphocyte, and epithelial cells Monocyte, myeloid stem cell, and ? Human herpesvirus 6 Herpes lymphotropic virus Lymphocytes and ? T cells and ? Close contact, transfusions, tissue transplant, and congenital Saliva Human herpesvirus 7 Human herpesvirus 7 Like human herpesvirus 6 T cells and ? Saliva REPLICATION • The virus enters the cell by fusion with the cell membrane after binding to specific cellular receptors via envelope glycoproteins. • Virus attachment also involves binding to one of several coreceptors (eg, members of the immunoglobulin superfamily). • After fusion, the capsid is transported through the cytoplasm to a nuclear pore, uncoating occurs, and the DNA becomes associated with the nucleus. • The viral DNA forms a circle immediately upon release from the capsid. • Expression of the viral genome is tightly regulated and sequentially ordered in a cascade fashion. • VP16, a tegument protein, complexes with several cellular proteins and activates initial viral gene expression. REPLICATION • Immediate-early genes are expressed, yielding “α” proteins. These proteins permit expression of the early set of genes, which are translated into “β” proteins. • Viral DNA replication begins, and late transcripts are produced that give rise to “ ” proteins. • More than 50 different proteins are synthesized in herpesvirus-infected cells. • Many α and β proteins are enzymes or DNAbinding proteins; most of the proteins are structural components REPLICATION • Viral DNA is transcribed throughout the replicative cycle by cellular RNA polymerase II but with the participation of viral factors. • Viral DNA is synthesized by a rolling-circle mechanism. • Herpesviruses differ from other nuclear DNA viruses in that they encode a large number of enzymes involved in DNA synthesis. These enzymes have been good targets for development of antiviral drugs. • Newly synthesized viral DNA is packaged into preformed empty nucleocapsids in the cell nucleus. • Maturation occurs by budding of nucleocapsids through the altered inner nuclear membrane. Enveloped virus particles are then transported by vesicular movement to the surface of the cell. REPLICATION • The length of the replication cycle varies from about 18 hours for HSV to more than 70 hours for CMV. • Cells productively infected with herpesviruses are invariably killed. • Host macromolecular synthesis is shut off early in infection; normal cellular DNA and protein synthesis virtually stop as viral replication begins. • Cytopathic effects induced by human herpesviruses are quite distinct and can include intranuclear inclusion bodies. Overview of Herpesvirus Diseases • A wide variety of diseases are associated with infection by Herpesviruses. • Primary infection and reactivated disease by a given virus may involve different cell types and present different clinical pictures. Overview of Herpesvirus Diseases • HSV-1 and HSV-2 infect epithelial cells and establish latent infections in neurons. • Type 1 is classically associated with oropharyngeal lesions and causes recurrent attacks of “fever blisters.” • Type 2 primarily infects the genital mucosa and is mainly responsible for genital herpes, though the anatomical specificity of these viruses is diminishing. • Both viruses can also cause neurologic disease. – HSV-1 is the leading viral cause of sporadic encephalitis in the United States. – Both types 1 and 2 can cause neonatal infections that are often severe. • VZV causes chickenpox (varicella) on primary infection and establishes latent infection in neurons. Upon reactivation, the virus causes herpes zoster (shingles). • Adults who are infected for the first time with varicella-zoster virus can develop serious viral pneumonia. Overview of Herpesvirus Diseases • CMV replicates in epithelial cells of the respiratory tract, salivary glands, and kidneys and persists in lymphocytes. • It causes an infectious mononucleosis (heterophile antibody-negative). • In newborns, disseminated cytomegalic inclusion disease may occur. CMV is an important cause of congenital defects, neonatal hearing loss, and mental retardation. • EBV replicates in epithelial cells of the oropharynx and parotid gland and establishes latent infections in lymphocytes. • It causes infectious mononucleosis and can induce human lymphoproliferative disorders, especially in immunocompromised patients Overview of Herpesvirus Diseases • HHV-6 infects T lymphocytes. It is typically acquired in early infancy and causes exanthem subitum (roseola infantum) as well as infections in immunocompromised patients. • HHV-7, also a T-lymphotropic virus, has not yet been linked to any specific disease. • HHV-8 is associated with the development of Kaposi sarcoma, a vascular tumor that is common in patients with AIDS. • Herpes B virus of macaque monkeys can infect humans upon exposure to live animals or tissue samples. Such infections are rare, but those that occur usually result in severe neurologic disease and are frequently fatal. Overview of Herpesvirus Diseases • Human herpesviruses are frequently reactivated in the elderly and immunosuppressed patients and may cause severe disease, such as pneumonia or lymphomas. • Herpesviruses have been linked with malignant diseases in humans and lower animals: – EBV with Burkitt lymphoma of African children, with nasopharyngeal carcinoma, and with other lymphoproliferative disorders; – KSHV with Kaposi sarcoma; – Marek disease virus with a lymphoma of chickens; and a number of primate herpesviruses with reticulum cell sarcomas and lymphomas in monkeys. Herpes Simplex Viruses • Herpes Simplex Viruses Type 1 • Herpes Simplex Viruses Type 2 Herpes Simplex Viruses • Distinct HSV-1 and HSV-2 • Differentiated restriction enzyme assay of DNA • Extremely widespread-humans • Broad host range- replicate in many different types of cells and infect different animals. Humans are the only natural hosts • Grow rapidly- highly cytolytic • Spectrum of diseases- gingivostomatitis, keratoconjunctivitis, encephalitis, genital diseases • Infections of newborns • Latent infection- nerve cells Herpes Simplex Viruses LATENCY • Escape immune response • Persist lifelong in latent state Normal humans → mostly trigeminal ganglia To some extent: cervical, sacral, vagal ganglia • Virus persistence → low grade productive virus infection → no lysis • True latency →virus non replicative Herpes Simplex Viruses REACTIVATION • Stress Physical/ psychological • Pneumococcal infection • Meningococcal infection • Fever • Irradiation • Menstruations • Immunosuppression • Cytotoxic drugs • HIV • Organ graft etc Transmission of HSV • Herpes simplex virus infections are very contagious and are spread by direct contact with the skin lesions. • Saliva HSV 1 • Respiratory route HSV 1 • Sexual contact HSV 2 HSV Clinical manifestation • Oropharyngeal disease-HSV-1 • Keratoconjunctivitis-HSV-1 • Genital herpes-HSV-2, though HSV-1too • Skin infections-HSV-1 and HSV-2 • Encephalitis-sporadic fatal-HSV-1 • Neonatal Herpes-from mother- HSV-2, from other contacts HSV-1 & HSV2 • Immunocompromised hosts • people who have HSV infections may be contagious even when they do not have any skin lesions, which is called asymptomatic shedding HSV Clinical manifestations Cold sore of recurrent herpes labialis HSV 1 COLD SORE HSV-1 COLD SORE HSV 1-Lesions around eye HSV Clinical manifestations A Primary herpes gingvostomatitis B HSV latent infection-trigeminal ganglia Herpes whitlow (Herpes skin infection) HSV 1-Lesions on Finger HSV-2 Genital Herpes • • • • • • • • • Usually HSV- 2 Primary infection severe-3 weeks Vesiculcerative lesions of penis-male Cervix, vulva,vagina,perineum-females Very painful Fever, malaise, dysuria, Lymphadenopathy Recurrence common-mild Sexual partners, mother-infant pairs, or persons involved in a common source of outbreak Genital Herpes simplex Typical Lesion on Penis Genital Herpes simplex Typical Lesion on Penis HSV-Penis- Healing Genital Herpes simplex Typical Lesion on Penis Genital Herpes-Female HSV and Immunity • • • • New born-passive 6 months 6 mo-2 y-highly susceptible Transplacental antibodies↓ infection Primary infection →antibodies +virus↓ latency • Recurrent → antibodies change/modify subsequent disease • Both antibody-mediated and cell-mediated reactions are clinically important. Diagnosis of HSV • Light microscopy-intranuclear inclusions infected cell →ballooning & fusion • Electron microscopy ? • Antigen detection • Virus culture-HSV 1, HSV 2 easiest to culture typical CPE • Serology –Antibodies-4-7 d after infection CFT/ IHA/ELISA/RIA • Restriction endonuclease analysis of viral DNA or DNA sequencing can be used to distinguish between the two types and among strains of each subtype. Is there any treatment for herpes? • There is no treatment that can cure herpes, • but antiviral medications can shorten and prevent outbreaks during the period of time the person takes the medication. • In addition, daily suppressive therapy for symptomatic herpes can reduce transmission to partners Antiviral chemotherapy for HSV Infections • Inhibit DNA synthesis-inhibit viral replication • Acyclovir-drug of choice • Famiclovir • Valaciclovir better absorption • Idoxyuridine • Vidarbine HSV Vaccines • Primary infection not worth preventing – Only experimental • Vaccines- purified glycoprotein ag – Recombinant HSV 2 subunit vaccines – Synthetic peptides THANK YOU NEXT LECTURE OTHER HERPES VIRUSES HUMAN HERPES VIRUS TYPE-3 VARICELLA- ZOSTER VIRUS • Two almost universal human diseases – 1. Chickenpox (Varicella)- exanthema of childhood – 2. Herpes zoster (Shingles) Disabling disease of aged persons or immunocompromised patients Varicella-Zoster • Varicella-Chicken pox ↓ • • • • • • • Latency ↓ Zoster-Shingles VZ virus causes two distinct clinical entities Both diseases same virus Morphologically identical to HSV Only one serotype-x HSV No animal reservoir (except primates) Grow readily in cell culture Intranuclear inclusions, balooning, swelling Varicella-Zoster Virus Normal individuals • Primary infection (chickenpox) is one of the classical rash diseases of childhood. • Following primary infection, the virus remains latent in the cranial-spinal ganglia. • Reactivation leading to the appearance of shingles occurs in 10-20% of infected individuals and usually occurs after the fourth decade of life. Usually, only one episode of reactivation occurs. Chicken pox. Each lesion has its own red base Chicken pox-lesions in various stages Varicella-Zoster Virus Immunocompromised individuals • Primary infection – severe in children -anti malignancy drugs- leukaemia and lymphoma. – Life-threatening complications such as disseminated varicella, pneumonia, and encephalitis are much more likely to be seen. • Reactivation – Immunocompromised →herpes zoster, appear at an earlier age and more than one episode may occur. – Severe, disseminated disease may occur but fatality is rare.