Herpes Viruses - Chapter 2 PDF

Herpes viruses Dr. Elie Salem Sokhn, PhD 1  HERPESVIRUSES Three subfamilies: Alphaherpesvirinae Gammaherpesvirinae Betaherpesvirinae Different in their: - genome structure - tissues tropism - cytopathologic effect - site of latent infection - diseas...

Herpes viruses Dr. Elie Salem Sokhn, PhD 1  HERPESVIRUSES Three subfamilies: Alphaherpesvirinae Gammaherpesvirinae Betaherpesvirinae Different in their: - genome structure - tissues tropism - cytopathologic effect - site of latent infection - disease manifestation Herpesvirus Evolutionary Tree  tegument 150 nm 162 capsomeres  Other features of HERPESVIRUSES Infections are common and distributed worldwide Important human pathogens that cause a wide spectrum of disease Cause lifelong, persistent infections Benign disease, especially in children Severe disease in immunosuppressed patients Linear genome containing direct and inverted repeats (UL and US) UL and US undergo orientation switch by recombination leading to isomeric genomes  Herpesvirus genomes Number of isomeric forms Purple bars indicate direct repeat DNA sequences; green bars indicate inverted repeated DNA sequences.  Herpesvirus: genome packaging Genome Packaging Herpesvirus genome a Replication a Genome concatamers DNA enters viral capsids Specific cleavage substrate mature virion cleavage and packaging A concatemer is a long continuous DNA molecule that contains multiple copies of the same DNA sequence linked in series.  Herpesviruses: Epidemiology Virus % Adults Seropositive HSV-1 70-90 HSV-2 30 VZV 95 EBV 95 HCMV 80 HHV-6 ~100 HHV-7 ~100 HHV-8 15  Persistent Herpesvirus Infections Latency established during primary infection - Suppression of cytolytic activities - Avoidance of host antiviral defenses Recurrent infections (reactivation from latency) - Intermittent (e.g., HSV, VZV) - Continuous (e.g., EBV)  Herpesvirus Genomes Double-stranded, linear DNA 70 to >200 genes Herpes Simplex Virus (HSV)  Herpes Simplex Virus (HSV) Two types: HSV-1 and HSV-2 HSV-1 and HSV-2 share antigenic determinants (cross-reactive antigens), tissues tropism and symptoms Genomes ~152 kbp Similar genomic organization ~50% DNA sequence homology  Replication of Herpes Simplex Virus Infects most types of human cells Causes lytic infection in fibroblasts and epithelial cells and latent infection in neurons Receptor = heparan sulfate found on the outside of many cells Coreceptor = nectin-1α (adhesion molecule) Envelope contains 10 glycoproteins (gB, gC, gD, gE, gH…) gC depletes C3 complement component and gE/gI complex links to Fc Ig fragments  Replication of Herpes Simplex Virus Immediate early gene products include transcription promotors Early proteins include DNA-dependent DNA polymerase and thymidine kinase and cell DNA and RNA synthesis inhibitor proteins Genome is replicated in an end-to-end concatameric form Replication triggers transcription of late proteins (structural) transported to the nucleus to form empty capsids (procapsids) Concatamers are cleaved into individual genomes as the DNA is sucked into procapsids Capsid buds into endoplasmic reticulum and Glogi where proteins are glycosylated, enzymes associated to capsids and teguments enclosed into an envelop.  Pathogenesis of Herpes Simplex Virus : Primary Infections HSV-1 and HSV-2 pathogenesis is similar Replicate in the mucoepithelial cells and cause disease locally HSV-1 is associated with infections above the waist and HSV-2 below the waist Pathogenesis of Herpes Simplex Virus: Primary Infections HSV-1 and HSV-2 cause lytic infections of most cells and latent infection of neurons Cytolysis results from: - inhibition of cellular molecule synthesis - degradation of host cell DNA and margination of chromatin (Cowdry type A acidophilic inclusion bodies) - cytoskeletal disruption - senescence of the cell Cell-mediated immunity controls the spread of the virus Cell to cell transmission escaping the antibody control Many strains initiate syncytia Pathogenesis of Herpes Simplex Virus: latency Neurons of the peripheral nervous system infected with virus released from epithelial cells Retrograde spread of nucleocapsids within axons Latency established in the cell bodies of dorsal root ganglia  Pathway of HSV Infection HSV enters HSV lies dormant HSV is reactivated, the body in the nerves causing another outbreak HSV enters body through After initial infection, HSV HSV travels along a break in the skin or settles in the sacral ganglia the nerves, back to the mucous membranes skin to form new blisters Counseling Guide and Patient Information. GlaxoSmithKline; 2000 Neurons Highly polarized cells. Axons transmit nerve impulses via synaptic vesicle formation & release. Dendrites provide a large surface area to receive nerve signals. Flint. Fig. 12.14. Page 435. HSV-1 : Axonal Transport Flint. Fig. 12.15. Page 436.  HSV-1 Latency 1. Molecular characteristics: - Genome persists - No protein expression. - Only a single promoter is active, expresses high levels of a non-coding transcript: LAT (latency-associated transcript). The function of LATs is uncertain, but they may play a role in inhibiting lytic gene expression. 2. Reactivation: No viral genes appear to be necessary for establishment of latency, but several are required for reactivation from latency Reactivation of Herpes Simplex Viruses Virus released from axon termini infects epithelial cells Anterograde spread of nucleocapsids within axons Virus reactivates from latency and replicates within the nuclei of dorsal root ganglia  Pathogenesis of Herpes Simplex Virus : Primary Infections Painful but benign disease Clear vesicle on an erythematous base “dewdrop on a rose petal” In immunosuppressed patient and neonate disseminated infection Serious forms in eye and brain infections (the most common viral cause of sporadic encephalitis) Recurrences are preceded by a characteristic prodrome of burning in the area of the future lesion eruption Recurrent episodes are less severe more localized and shorter in duration Primary Herpes Cold sore of recurrent gingivostomatitis Herpes labialis Vesicles-ulcers-crusting Small vesicles Anywhere in the oral cavity Occur only on the hard palate and gingiva, corners of the mouth or next to the lips  Herpesvirus Infection Primary Infection  Herpesvirus Infection Primary Infection  Herpesvirus Infection Secondary infection Herpesvirus Infection Genital infections Herpesvirus Infection Whitlow Herpesvirus Infection Ocular lesions  Herpesvirus Infection Neonatal Manifestations: Disseminated HSV infection 60% mortality – Localized encephalitis 14% mortality – Dermatologic, Ocular, and Oral infections Clinical course of Genital Herpes infection Prophylaxis of Herpes Simplex Virus Major source of whitlow in health care personnel Patients with herpes history must refrain from sexual intercourse during prodromal symptoms Pregnant women are advised to undergo cesarean section No vaccine is currently available. Varicella-Zoster Virus VZV  Varicella-Zoster Virus Causes chikenpox (varicella) Upon recurrence causes herpes zoster or shingles Unlike HSV, spreads through respiratory routes, local replication, viremia then skin lesions over the entire body Common characteristics with HSV: - Latent infections - Cell mediated immunity prevents serious disease - Blister lesions - Has a thymidine kinase and is susceptible to antiviral drugs  Varicella-Zoster Virus Smallest genome of herpesviruses Infects fewer types of cells than HSV: Fibroblasts, epithelial cells and activated lymphocytes Pathogenesis of Varicella-Zoster Virus Virus replicates in the lung and is a major source of contamination Virus progresses via the bloodstream and lymphatics to the reticuloendothelial system Secondary viremia occurs after 2 weeks and spreads the virus throughout the body and the skin where it causes a rash of dermal vesiculopustular that develops overtime in successive crops. Immunocompromised patients and neonates show serious disease potentially fatal Clinical syndromes of Varicella-Zoster Virus Is one of the five classical childhood exanthems : rubella, roseala, fifth disease and measles. Typical Varicella vesicles start with macules then papules, vesicles, pustules and crust. Then Zoster (Shingles) Spread across the entire body but the presence of lesions on the scalp distinguishes it from other rashes Lesions itch and cause scratching, which may lead to bacterial superinfection Symptoms appear after an incubation period of two weeks Symptoms are more severe in adults than in children Interstitial pneumonia may occur in 20%-30% of adults due to an inflammatory reaction of the primary infection. Fever occur with the rash ± malaise and headache  Herpesvirus Infection Varicella zoster virus  Herpesvirus Infection Varicella zoster virus VZV: Zoster (Shingles) Shingles  VZV: Zoster (Shingles) http://www.ihmf.org/OnlineLearningZone/DiagnosticAtlas.asp 2256. Herpes zoster. Vesicles in a dermatomal distribution, characteristic of herpes zoster. Pathogenesis of Varicella-Zoster Virus: latency Cell-mediated immunity controls the spread of the virus but is responsible of the symptoms Perform cell to cell transmission and syncytia. Antibodies can still limit the spread which helps in resolving the disease Virus becomes latent in the ganglia When the virus is reactivated, it replicates and is released along the entire neural pathway causing rash along the entire dermatome called Zoster (belt). In patients older than 65 years, herpes zoster may become a chronic painful syndrome that lasts months or years called Postherpetic neuralgia. 2257 - Tzank smear of herpes zoster. This Tzank smear is made by scraping the base of a herpetic blister. Both herpes simplex and herpes zoster show similar features of multinucleated giant cells, ballooning of the nucleus, margination (peripheral clumping of chromatin) and ground glass nuclear inclusion (arrow).  Treatment of Varicella-Zoster Virus Drug therapy is valid only for Immunocompromised patients and zoster cases. VZIg is valid only for Immunocompromised patients Epstein-Barr Virus EBV  Features of Epstein-Barr Virus B lymphocytes and epithelial cells are the unique targets of EBV EBV was discovered by electron-microscopic observation of characteristic herpes virions in biopsy specimens of a B-cell neoplasm, African Burkitt lymphoma (AfBL). Its association with infectious mononucleosis was discovered accidentally when serum collected from a laboratory technician convalescing from infectious mononucleosis was found to contain the antibody that recognized AfBL cells. Discovery confirmed in a large serologic studies  Features of Epstein-Barr Virus Distributed worldwide >90-95% of the population infected by adulthood Causes lifelong, persistent infections and the majority is benign Causes heterophile antibody-positive infectious mononucleosis. Epstein-Barr Virus structure and replication EBV receptor is the receptor for the C3d component of the complement system (CR2) CD21. CD21 is expressed on B cells and some epithelial cells of the oropharynx and nasopharynx EBV uses the MHC class II as co-receptor EBV infection has three potential outcomes: - Replication - Latency - Immortalization of B cells Epstein-Barr Virus replication and life cycle Epstein-Barr Virus structure and replication Genome encodes for 70 proteins During non productive infection cells contain plasmidelike EBV genomes that replicates only during cell division and express selective genes with a role in immortalization: - Epstein-Barr Nuclear Antigens (EBNAs) - Latent Proteins (LPs) - Latent Membrane Proteins (LMPs) Proteins of productive infection are serologically grouped as: - Early Antigen (EA) - Viral Capsid Antigen (VCA) - Membrane Antigens (MA) EBV Latency Proteins Cohen NEJM 2000  Pathogenesis of Epstein-Barr Virus Infection of B cells establishes lifelong infection and disease results from either an overactive immune response and leads to infectious mononucleosis or from the lack of effective immune control: lymphoma and hairy cell leukoplakia Productive infection of B cells and epithelial cells of the oropharynx promotes virus shedding into saliva to transmit the virus to other hosts EBV proteins activate B-cell growth and also prevent apoptosis, leading to non specific IgM production (heterophile antibodies) Continued B-cell proliferation in conjunction with the effects of other cofactors may result in the development of lymphoma  Pathogenesis of Epstein-Barr Virus In the absence of T cells (tissue culture), EBV can immortalize B cells and promote the development of B- lymphoblastoid cell lines. Infectious mononucleosis results from a reaction between the EBV-infected B cells and the protective T cells, where T cells are activated by infected APCs. Activation and proliferation of T cells yield a lymphocytosis (swelling of nodes, spleen and liver) where atypical T cells appear (Downey cells) accounting to 10-80% of WBC count. Children have a less active immune response Latent viruses in memory B cells will be activated when the B cells is challenged with the antigen Atypical T cells (Downey cells)  Epidemiolgy of Epstein-Barr Virus EBV is transmitted in Saliva More than 90% of EBV infected people intermittently shed the virus for life even when asymptomatic Children acquire the virus at an early age by sharing contaminated drinking glasses. Disease may go unnoticed or may manifest in varying degrees of severity. Adolescents acquire the virus during kissing (Kissing disease) disease is usually more frequent and more severe than in children Kissing disease  Herpesviruses: Epidemiology Virus % Adults Seropositive HSV-1 70-90 HSV-2 30 VZV 95 EBV 95 HCMV 80 HHV-6 ~100 HHV-7 ~100 HHV-8 15 Clinical syndromes of Infectious mononucleosis Clinical syndromes of Epstein-Barr Virus Infectious mononucleosis classical symptoms TRIAD: - Lymphadenopathy - Fever - Deep fatigue - Splenomegaly - Pharyngitis ±, malaise, hepatomegaly, rash, and rarely neurologic disorders and rupture of the spleen. Constant presence of Heterophile antibodies. Mononucleosis-like syndromes can also be caused by CMV, HHV6 and Toxoplasma gondii without Heterophile antibodies. Pathogenesis of Epstein-Barr Virus Clinical syndromes of Epstein-Barr Virus Congenital deficiencies, transplanted patients and AIDS lack T-cell immunity and may suffer life-threatening polyclonal leukemia-like B-cell proliferative disease and lymphoma instead of Infectious mononucleosis. (PTLD: Post-transplant lymphoproliferative disorders) African Burkitt’s lymphoma is endemic in children living in the malarial regions of Africa ? Many Hodgkin’s lymphomas can also be attributed to EBV Epithelial nasopharyngeal carcinoma containing EBV DNA in Asian adults were also reported Productive EBV infection of epithelial cells characterized by lesions of the mouth are also reported in AIDS patients: Hairy Oral Leukoplakia. Diseases Associated with EBV EBV in B Cell Infectious mononucleosis X-Linked Lymphoproliferative Disease Chronic active EBV Hodgkin Disease Burkitt Lymphoma Lymphoproliferative disease EBV in Other Cells Nasopharyngeal carcinoma Gastric carcinoma Nasal T/NK cell lymphomas Peripheral T cell lymphomas Oral hairy leukoplakia Smooth muscle tumors in transplant patients Clinical syndromes of Epstein-Barr Virus http://www.nib.unicamp.br/cov/casos/caso9/b urkit_e1.htm Burkitt’s lymphoma Burkitt's lymphoma (jaw tumors) Burkitt's lymphoma Nasopharyngeal carcinoma  What evidence supports a causal role for EBV in the development of BL? 1. Close association 2. Seroepidemiology 3. Ability of EBV to drive proliferation of B cells in culture 4. Ability of EBV to drive proliferation of B cells in vivo (immunoblastic B-cell lymphoma)  LMP-1 is the EBV Oncogene Oncogene: Expression in transgenic mice leads to B cell lymphoma; expression in fibroblasts leads to tumors in nude mice B Cell Proliferation Upregulates adhesion molecules, CD23, CD40, IL-6, IL- 10, etc. Activates NF-B (nuclear factor kappa-light- chain-enhancer of activated B cells) Inhibits apoptosis Upregulates Bcl-2, A20, Mcl-1  Treatment of Epstein-Barr Virus No treatment or vaccine is available EA, Early antigen EBNA, Epstein-Barr nuclear antigen VCA, viral capsid antigen. Human Cytomegalovirus Virus HCMV Features of Human Cytomegalovirus Virus The most common viral cause of congenital defects Causes mild or asymptomatic disease Typical opportunistic virus in immunocompromised patients Human Cytomegalovirus structure and replication HCMV infects mainly epithelial cells, fibroblasts, macrophages and lymphocytes. HCMV infection has two potential outcomes - Replication in epithelial cells, fibroblasts - Latency in lymphocytes and macrophages Pathogenesis of Human Cytomegalovirus HCMV is acquired from blood, tissues and most body secretions In most cases, HCMV replicates and is shed without causing symptoms (subclinical) The virus is reactivated by immunosuppression Cell mediated immunity is required for disease resolution and contributes to symptoms Clinical syndromes of Human Cytomegalovirus Congenital infection (prior to birth), can cross placenta, 10% of infected newborns show: - small size - Thrombocytopenia - Rash (cytomegalo inclusion disease) - Unilateral or bilateral hearing loss - Mental retardation The risk for these serious defects is higher when mothers undergo a primary infection during pregnancy Perinatal infection (during and after delivery): usually show no symptoms, Rash is possible Cytomegalo inclusion Clinical syndromes of Human Cytomegalovirus Infected children and adults: - Usually show no symptoms - Hetrerophile-negative Infectious Mononucleosis syndrome Transmission via Transfusion and Transplantation - Hetrerophile-negative Infectious mononucleosis syndrome - Pneumonia and mild hepatitis Immunocompromised host: - Pneumonia and pneumonitis that could be fatal - Retinitis - Esophagitis - Colitis (usually with diarrhea) - Failure of transplants  Herpesviruses: Epidemiology Virus % Adults Seropositive HSV-1 70-90 HSV-2 30 VZV 95 EBV 95 HCMV 80 HHV-6 ~100 HHV-7 ~100 HHV-8 15 Treatment of Cytomegalovirus infections Virus lacks TK. Acyclovir is inefficient and must treat with ganciclovir in pneumonia and retinitis in immunocompromised persons Foscarnet: HCMV disease in bone marrow transplant recipients (Noncompetitive inhibitor of the herpesviral DNA polymerase. Causes kidney toxicity; use limited to life-threatening infections). No available vaccine Human Herpes Virus 6 (HHV6) Human Herpes Virus 6 (HHV6)  Human Herpesvirus-6 Two closely-related viruses (HHV-6A and -6B). Usually acquired during infancy/early childhood. Causative agent of exanthem, commonly known as roseola, generalized rash that lasts only 24 to 48 hours, febrile illness with high fever. Transmitted to susceptible host via saliva, frequently found in saliva of adults. Like CMV, it infects lymphocytes, macrophages, monocytes, kidney tubule endothelial cells and salivary glands. The presence of infected T cells or the activation of type IV hypersensitivity T cells in the skin may be the cause of the rash Latency established in T cells, macrophages. Attaches to Membrane Cofactor Protein (MCP) present on most cells. (complement factor)  HHV-6 and Multiple Sclerosis HHV-6 has been associated with multiple sclerosis (controversial findings) Presence of HHV-6 in MS plaques and non-plaque regions of white matter from MS patients (but not from tissue from patients without MS) demonstrated by immunohistochemistry Increased antibody response to HHV-6 in serum and CSF of MS patients HHV-6 DNA in serum of MS patients but not normal persons Human Herpes Virus 7 (HHV7)  Human Herpesvirus-7 Not known to cause disease in humans  Human Herpes Virus 8 (HHV8) or Kaposi’s Sarcoma-Associated Herpesvirus (KSHV)  Human Herpesvirus-8 Present in most, if not all, Kaposi’s sarcomas (15-25% of male homosexual, HIV-1-positive men develop Kaposi’s sarcoma) Like EBV, the B cell is the primary target cell for HHV8, but also infects endothelial and epithelial cells. Found in the endothelial and spindle cells of Kaposi’s lesions Predominantly a latent infection Most likely transmitted sexually.