Herpes Viruses

MICROBIOLOGY

Dra. Bunyi

Herpesviruses

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PROPERTIES OF HERPESVIRUSES enveloped double stranded DNA viruses genome: long and short fragments oriented in either direction, giving a total of 4 isomers set up latent or persistent infection following primary infection Reactivation – more likely during periods of immunosuppression Both primary infection and reactivation are likely to be more serious in immunocompromised patients 3 subfamilies: 1. Alphaherpesviruses – HSV-1, HSV-2, VZV; rapid growth, latency in sensory ganglia 2. Betaherpesviruses – CMV, HHV-6, HHV-7; slow growth; restricted host range 3. Gammaherpesviruses – EBV, HHV-8; growth in lymphoblastoid cells

HERPESVIRUS PARTICLE ALL herpesviruses have identical morphology and cannot be distinguished from each other under electron microscopy. HERPES SIMPLEX VIRUS PROPERTIES:  Belong to the α-herpesvirus subfamily of herpesviruses  Double stranded DNA enveloped virus with a genome of around 150 kb  The genome of HSV-1 and HSV-2 o Share 50-70% homology o Share several cross-reactive epitopes with each other o Also antigenic cross-reaction with VZV  Man is the only natural host for HSV EPIDEMIOLOGY:  HSV – spread by contact (shed in saliva, tears, genital and other secretions)  most common form of infection result from a KISS given to a child or adult from a person shedding the virus  primary infection: o usually trivial or subclinical in most individuals o disease mainly of very young children (<5 years)  two peaks of incidence: o 0-5 years o Late teens (sexual activity commences)  10% of the population acquires HSV infection through the genital route and the risk is concentrated in young adulthood  Generally: o HSV-1 causes infection above the belt o HSV-2 below the belt  Clinical isolates: o 40% from genital sores are HSV-1 o 5% of strains isolated from the facial area are HSV-2 (data is complicated by oral sexual practices)  Following the primary infection, 45% of orally infected individuals and 60% of patients with genital herpes will experience recurrences  Actual frequency of recurrences varies widely between individuals

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shar, cams, joy

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Mean number of episodes per year: 16

PATHOGENESIS:  Primary infection, HSV spreads locally and a shortlived viremia occurs, whereby the virus is disseminated in the body. Spread to the craniospinal ganglia occurs.  The virus then establishes latency in the craniospinal ganglia.  The exact mechanism of latency is not known. It may be true latency where there is no viral replication or viral persistence where there is a low level of viral replication.  Reactivation – triggers can provoke a recurrence. These include: o Physical or psychological stress o Infection, especially pneumococcal and meningococcal o Fever o Irradiation, including sunlight o Menstruation CLINICAL MANIFESTATIONS: HSV is involved in a variety of clinical manifestations which includes:  Acute gingivostomatitis  Herpes labialis (cold sore)  Ocular herpes  Herpes genitalis  Other forms of cutaneous herpes  Meningitis  Encephalitis  Neonatal herpes ACUTE GINGIVOSTOMATITIS  Commonest manifestation of primary herpetic infection  Manifestations: pain and bleeding of the gums o 1-8 mm ulcers with necrotic bases are present o Neck glands are commonly enlarged accompanied by fever  Usually a self-limiting disease which lasts around 13 days HERPES LABIALIS (COLD SORE)  Following primary infection, 45% of orally infected individuals will experience reactivation  Herpes labialis is a recurrence of oral HSV  A prodrome of tingling, warmth or itching at the site usually heralds the recurrence. About 12 hours later, redness appears followed by papules and then vesicles. OCULAR HERPES HSV causes a broad spectrum of ocular disease, ranging from mild superficial lesions involving the external eye to severe sight-threatening diseases of the inner eye. Diseases caused include the following:  Primary HSV keratitis – dendritic ulcers  Recurrent HSV keratitis  HSV conjunctivitis  Iridocyclitis, chorioretinitis, and cataract GENITAL HERPES  Genital lesions may be primary, recurrent, or initial 1of 6

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Sites: penis, vagina, cervix, anus, vulva, bladder, sacral nerve routes, spine and meninges o Lesions of genital herpes prone to secondary bacterial infection o E.g., S. aureus, Streptococcus, Trichomonas, C. albicans Dysuria: common complaint; in severe cases, there may be urinary retention Local sensory nerves may be involved leads to radiculitis A mild meningitis may be present 60% of patients with genital herpes will experience recurrences. Recurrent lesions in the perianal areas tend to be more numerous and persists longer than their oral HSV-1 counterpart.

HERPES SIMPLEX ENCEPHALITIS  One of the most serious complications of HSV disease  2 forms: o Neonatal: global involvement; brain is almost liquefied; mortality rate approaches 100% o Focal disease: temporal lobe most commonly affected; appears in children and adults; arise from reactivation of virus; mortality rate is high (70%) without treatment  Utmost importance: make a diagnosis of HSE early o IV acyclovir: given in all cases of suspected of HSE before laboratory results are available NEONATAL HERPES SIMPLEX  Incidence varies from country to country o US: 1 in 4000 live births o UK: 1 in 10000 live births  Baby is usually infected perinatally during passage through the birth canal  Premature rupturing of the membranes is a well recognized risk factor  Risk of perinatal transmission: greatest when there is a florid primary infection in the mother  Smaller risk from recurrent lesions in the mother: lower viral load and the presence of specific antibodies  Other sources: oral lesions from the mother or a herpetic whitlow in a nurse  Spectrum: mild disease; localized to the skin  ftal disseminated infection  Infection: particularly dangerous in premature infants  Organs involved in disseminated disease: o Liver, adrenals and the brain o Brain involvement: prognosis is severe  Encephalitis is global; brain may be liquefied  Survivors: residual disabilities  Acyclovir should be promptly given in all suspected cases of neonatal HSV infection  Only means of prevention: offer C-section to mothers with florid genital HSV lesions OTHER MANIFESTATIONS:  Disseminated herpes simplex: more likely to occur in immunocompromised individuals o Vesicular lesions resembles that of chicken pox o Involved organs other than skin: liver, spleen, lungs, CNS  Other cutaneous manifestations include: o Eczema herpeticum: potentially a serious disease that occurs in patients with eczema

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Herpetic whitlow: arise from implantation of the virus into the skin and typically affect the fingers Zosteriform herpes simplex: rare presentation of herpes simplex where HSV lesions appear is a dermatomal distribution similar to herpes zoster

LABORATORY DIAGNOSIS:  Direct detection: o EM of vesicle fluid: rapid result but cannot distinguish between HSV and VZV o IF of skin scrapings: can distinguish between HSV and VZV o PCR: diagnosis of herpes simplex encephalitis  Virus isolation: o HSV-1 and HSV-2 are among the easiest viruses to cultivate; takes only 1-5 days  Serology: o Not that useful in the acute phase because it takes 1-2 weeks for before antibodies appear after infection. Used to document to recent infection. MANAGEMENT: General indications for antiviral chemotherapy:  Where the primary infection is especially severe  Where there is dissemination  Where sight is threatened  Herpes simplex encephalitis Acyclovir – DOC for most situations at present. Available formulations:  IV (HSV infection in normal and immunocompromised patients)  Oral (treatment and long term suppression of mucocutaneous herpes and prophylaxis of HSV in immunocompromised patients)  Cream )HSV infection of the skin and mucus membranes)  Ophthalmic ointment Famiciclovir and Valacyclovir – oral only, more expensive than acyclovir Other older agents – e.g., idoxuridine, trifluorothymidine, vidarabine (ara-A)  These agents are highly toxic and is suitable for topical use for ophthalmic infection only. VARICELLA-ZOSTER VIRUS PROPERTIES:  Belong to the herpesvirus subfamily of herpesviruses  Double stranded DNA enveloped virus  Genome size is 125 kbp, long and short fragments with a total of 4 isometric forms  One antigenic serotype only, although there is some cross reaction with HSV EPIDEMIOLOGY:  Primary varicella is an endemic disease; classic diseases of childhood o Highest prevalence: 4-10 y/o age group  Varicella is highly communicable, attack rate of 90% in close contacts  Most people become infected before adulthood but 10% of young adults remain susceptible  Herpes zoster: occurs sporadically and evenly throughout the year PATHOGENESIS: 2of 6

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Entry via the respiratory tract and spreads to the lymphoid system After an IP of 14 days, the virus arrives at its main target organ, the skin Following the primary infection, the virus remains latent in the cerebral or posterior root ganglia o In 10-20% of individuals, a single recurrent infection occurs after several decades Virus reactivates in the ganglion and tracks down the sensory nerve to the area of the skin innervated by the nerve, producing a varicella form rash in the distribution of the dermatome

VARICELLA  Primary infection results in varicella (chickenpox)  IP of 14-21 days  Manifestations: o Fever, lymphadenopathy, a widespread vesicular spread  Clinical features are characteristic o Diagnosis made on clinical grounds alone  Complications are rare o Occurs more frequently and with greater severity in adults and immunocompromised patients  Most common complication: secondary bacterial infection  Severe complications: life threatening – viral pneumonia, encephalitis, and hemorrhagic chickenpox HERPES ZOSTER (SHINGLES)  Herpes zoster mainly affect a single dermatome of the skin  May occur at any age; majority of patients are >50 y/o  Latent virus reactivates in a sensory ganglion and tracks down the sensory nerve to the appropriate segment  Eruption of vesicles in the dermatome is often accompanied by intense pain which may last for months (postherpetic neuralgia)  Herpes zoster affecting the eye and face may pose great problems  As with varicella, herpes zoster is a far greater problem in immunocompromised patients in whom the reactivation occurs earlier in life and multiple attacks occur as well as complications  Complications: rare and include encephalitis and disseminated herpes zoster CONGENITAL VZV INFECTION:  90% of pregnant women already immune, therefore, primary infection is rare during pregnancy  Primary infection during pregnancy carries a greater risk of severe disease, in particular, pneumonia  First 20 weeks of pregnancy: o 3% chance of transmission to the fetus o Recognized congenital varicella syndrome:  Scarring of skin  Hypoplasia of limbs  CNS and eye defects  Death in infancy normal NEONATAL VARICELLA  VZV can cross the placenta in the late stages of pregnancy to infect the fetus congenitally  Neonatal varicella: vary from a mild disease to a fatal disseminated infection

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If rash in mother occurs > 1 week before delivery, sufficient immunity transferred to the fetus VZIg should be given to susceptible pregnant women who had contact wit suspected cases of varicella VZIg should also be given to infants whose mothers develop varicella during the last 7 days of pregnancy or the first 14 days after delivery

LABORATORY DIAGNOSIS:  Clinical presentation: characteristic  Laboratory diagnosis: required only for atypical presentations, particularly in the immunocompromised o Virus isolation: rarely carried out; results available after 2-3 weeks o Direct detection – EM may be used for vesicle fluids but cannot distinguish between HSV and VZV o IF on skin scrapings can distinguish between the two o Serology: (+) VZV IgG – past infection and immunity (+) IgM – recent primary infection  Culture: cytopathic effect on cells MANAGEMENT:  Uncomplicated varicella: self-limited; no specific treatment o Acyclovir: accelerate the resolution of the disease o Indications:  Immunocompromised individuals  Individuals with serious complicationsL pneumonia and encephalitis  Herpes zoster in a healthy individual: not a cause for concern o Management of the postherpetic neuralgia can be problematic o The International Herpes Management Forum recommends that antiviral therapy should be offered routinely to all patients over 50 y/o presenting with herpes zoster o 3 drugs for the treatment of herpes zoster: acyclovir, valacyclovir, and famciclovir. There appears to be little difference in efficacy between them PREVENTION:  Preventive measures: considered at risk of contracting severe varicella infection e.g. leukemic children, neonates, and pregnant women  Where urgent protection is needed, passive immunization should be given o Varicella zoster immunoglobulin (VZIG) is the preparation of choice but is very expensive o A live attenuated vaccine is available  Safe, even in children with leukemia provided that they are in remission CYTOMEGALOVIRUS PROPERTIES:  Belong to the betaherpesvirus subfamily of herpesviruses  Double stranded DNA enveloped virus  Nucleocapsid 150 nm in diameter, 162 capsomers  Genomic structure of CMV is similar to other herpesviruses, consisting of long and short segments which may be oriented in either direction, giving a total of 4 isomers  A large number of proteins are encoded for, the precise number is unknown 3of 6

EPIDEMIOLOGY:  CMV: one of the most successful human pathogens o Can be transmitted vertically or horizontally usually with little effect on the host  Transmission may occur in utero, perinatally or postnatally  Once infected, the person carries the virus for life which may be activated from time to time, during which infectious virions appear in the urine and the saliva  Reactivation can also lead to vertical transmission  It is also possible for people who have experienced primary infection to be reinfected with another or the same strain of CMV, this reinfection does not differ clinically from reactivation  In developed countries with a high standard of hygiene, 40% of adolescents are infected and ultimately 70% of the population is infected  In developing countries, over 90% of people are ultimately infected PATHOGENESIS:  Once infected, the virus remains in the person for life o May be reactivated from time to time, especially in immunocompromised individuals  Transmission: in utero, perinatally, or postnatally. Perinatal transmission occurs  Perinatal infection: acquired mainly through infected genital secretions, or breast milk o 2-10% of infants infected by the age of 6 months o Perinatal infection: 10x more common than congenital infection  Postnatal infection mainly occurs through saliva. Sexual transmission may occur as well as through blood and blood products and transplanted organ. CLINICAL MANIFESTATIONS:  Congenital infection: result in cytomegalic inclusion disease  Perinatal infection: usually asymptomatic  Postnatal infection: usually asymptomatic o Minority of cases: a syndrome of infectious mononucleosis may develop – fever, lymphadenopathy, and splenomegaly. The heterophil antibody test (-); atypical lymphocytes may be found in the blood  Immunocompromised patients: transplant recipients and AIDS patients are prone to severe CMV disease such as pneumonitis, retinitis, colitis, and encephalopathy  Reactivation or reinfection with CMV is usually asymptomatic EXCEPT in immunocompromised patients CONGENITAL INFECTION:  Definition: isolation of CMV from the saliva or urine within 3 weeks of birth  Most common congenital viral infection; affects 0.3-1% of all live births  2 nd most common cause of mental handicap after Down’s syndrome; responsible for more cases of congenital damage than rubella  Transmission to the fetus may occur following primary or recurrent CMV infection o 40% chance of transmission to the fetus following a primary infection  May be transmitted to the fetus during all stages of pregnancy

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No evidence of teratogenicity, damage to the fetus results from destruction of target cells once they are formed

CYTOMEGALIC INCLUSION DISEASE  CNS abnormalities: o Microcephaly, mental retardation, spasticity, epilepsy, periventricular calcification  Eye: chorioretinitis and optic atrophy  Ear: sensorineural deafness  Liver: hepatosplenomegaly and jaundice due to hepatitis  Lung: pneumonitis  Heart: myocarditis  Thrombocytopenic purpura, hemolytic anemia  Late sequelae in individuals asymptomatic at birth: hearing defects and reduced intelligence INCIDENCE OF CYTOMEGALIC DISEASE: USA No. of live 3,000,000 births p.a. Rate of 1% Congenital CMV No. of Infected 30,000 Infants Symptomatic at 1,500 – 3,000 Birth (5-10%) Fatal Disease 300-600 (≈20%) No. With Sequelae (90% 1080-2160 of survivors) Asymptomatic 27,000 (90-95%) No. with Late 1,350-4,550 Sequelae

UK 700,000 0.3% 2,100 105 22 83 1,995 315

LABORATORY DIAGNOSIS:  Direct detection: o Biopsy specimens: histologic examination for CMV inclusion antibodies or for the presence of CMV antigens  Sensitivity may be low o The pp65 CMV antigenaemia test: routinely used for rapid diagnosis of CMV infection in immunocompromised patients o PCR for CMV-DNA: used in some centers but there may be problems with interpretation  Virus isolation o Conventional cell culture: gold standard  Requires up to 4 weeks for result o More useful: rapid culture methods such as the DEAFF test – provide a result within 24-48 hours  Serology: o (+) CMV IgG antibody: past infection o (+) CMV IgM antibody: primary infection; also found in immunocompromised patients with reactivation SPECIMENS FOR LABORATORY DIAGNOSIS: Site for Virus Culture

Neonates Adults Pregnant Women

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TREATMENT:  Congenital infections: not usually possible to detect congenital infection unless the mother has symptoms of primary infection. ? chances of her baby having CID o ? offer the choice of an abortion  Perinatal and postnatal infection: not necessary to treat such patients  Immunocompromised patients: early diagnosis of CMV infection and give prompt antiviral therapy o Anti-CMV agents in current use are ganciclovir, foscarnet, and cidofovir PREVENTION:  No licensed vaccine available: o Concern: administering a live vaccine which can become latent and reactivates  Prevention in transplant recipients: very complicated and varies from center to center. It may include the following measures: o Screening and matching the CMV status of the donor and recipient o Use of CMV negative blood for transfusions o Administration of CMV immunoglobulin to seronegative recipients prior to transplant o Give antiviral agents such as acyclovir and ganociclovir prophylatically EPSTEIN BARR VIRUS PROPERTIES:  Belong to the gammaherpesvirus subfamily  Nucleocapsid: 100 nm in diameter, 162 capsomers  Membrane is derived by budding of immature particles through cell membrane and is required for infectivity  Genome: linear double stranded DNA; 172 kbp  Viral genome does not normally integrate into the cellular DNA but forms circular epitomes which reside in the nucleus  The genome is large enough to code for 100-200 proteins but only a few have been identified EPIDEMIOLOGY:  Two epidemiological patterns seen with EBV  Developed countries: 2 peaks of infection o Preschool children aged 1-6 o Adolescents and young adults aged 14-20 o Eventually 80-90% of adults are infected  Developing countries: much earlier age so that by the age of 2, 90% of children are seropositive  Transmitted by contact with saliva (kissing) PATHOGENESIS:  Lifelong carrier stage develops once infected, whereby a low grade infection is kept in check by the immune defenses  Low grade virus replication and shedding: demonstrated in the epithelial cells of the pharynx of all seropositive individuals  EBV: able to immortalize B-lymphocytes in vitro and in vivo  Few EBV-immortalized B-cells can be demonstrated in the circulation which are continually cleared by the immune surveillance mechanisms  EBV is associated with several very different diseases where it may act directly or one of several co-factors

DISEASE ASSOCIATION: 1. Infectious Mononucleosis 2. Burkitt’s Lymphoma 3. Nasopharyngeal Carcinoma 4. Lymphoproliferative Disease and Lymphoma in the Immunosuppressed 5. X-linked Lymphoproliferative Syndrome 6. Chronic Infectious Mononucleosis 7. Oral Leukoplakia in AIDS Patients 8. Chronic Interstitial Pneumonitis in AIDS Patients INFECTIOUS MONONUCLEOSIS:  Primary EBV infection: o Usually subclinical in childhood o Adolescents and adults: 50% chance that the syndrome of IM will develop  IM: self-limiting disease – fever, lymphadenopathy and splenomegaly o In some: jaundice (due to hepatitis); (+) atypical lymphocytes in the blood  Complications: rare but may be serious o E.g. splenic rupture, meningoencephalitis, pharyngeal obstruction  Chronic IM may occur where eventually the patient dies of lymphoproliferative disease or lymphoma  Diagnosis of IM: heterophil antibody test and/or detection of EBV IgM  NO specific treatment BURKITT”S LYMPHOMA:  Burkitt’s lymphoma: occurs endemically in parts of Africa (most common childhood tumor) and Papua New Guinea o Usually seen in children age 3-14 years o Responds favorably to chemotherapy  Restricted to areas with holoendemic malaria. Therefore it appears that malaria infection is a cofactor.  Multiple copies of EBV genome and some EBV antigens can be found in BL cells and patients with BL have high titres of antibodies against various EBV antigens.  BL cells show a reciprocal translocation between the long arm of chromosome 8 and chromosomes 14, 2 or 22  This translocation result in the c-myc oncogene being transferred to the immunoglobulin gene regions  results in the deregulation of the c-myc gene. It is thought that this translocation is probably already present by the time of EBV infection and is not caused by EBV.  Sporadic cases of BL occur, especially in AIDS patients which may or may not be associated with EBV.  In theory, BL can be controlled by the eradication of malaria (as has happened in Papua New Guinea) or vaccination against EBV NASOPHARYNGEAL CARCINOMA (NPC):  Malignant tumor of the squamous epithelium of the nasopharync  Prevalent in South China: most common tumor in men and second common in women  Rare in most parts of the world, though pockets occur in North and Central Africa, Malaysia, Alaska, and Iceland  Multiple copies of EBV genome and EBV EBNA-1 antigen can be found in cells of undifferentiated 5of 6

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NPC. Patients with NPC have high titres of antibodies against various EBV antigens Environmental and genetic cofactors in NPC NPC usally presents late and thus the prognosis is poor In theory, NPC can be prevented by vaccination

IMMUNOCOMPROMISED PATIENTS:  After primary infection, EBV maintains a steady low grade latent infection in the body. Should the person become Immunocompromised, the virus will reactivate. o In some, lymphoproliferative lesions and lymphoma may develop. These lesions tend to be extranodal and in unusual sites such as the GI tract or the CNS  Transplant recipients: EBV is associated with the development of lymphoproliferative disease and lymphoma  AIDS patients: EBV is associated with oral leukoplakia and with various non-Hodgkin’s lymphoma  Ducan X-linked lymphoproliferative syndrome: occurs exclusively in males who had inherited a defective gene in the X chromosome. This condition accounts for half of the datal cases of IM. DIAGNOSIS:  Acute EBV Infection: heterophil antibody test and/or detection of anti-EBV VCA IgM  Burkitt’s lymphoma histolohy: tumor can be stained with antibodies to lambda light chains which reveal a monoclonal tumor of B-cell origin. In over 90% of cases, the cells express IgM at the cell surface  NPC: histology  The determination of the titre of anti-EBV VCA IgA in screening for earl lesions of NPC and also for monitoring treatment.  A patient with non-specific ENT symptoms who have elevated titres of EBV IgA should be given a thorough examination. VACCINATION:  A vaccine against EBV which prevents primary EBV infection should be able to control both BL and NPC  Must be given early in life; also useful in seronegative organ transplant recipients and those developing severe IM, such as the male offspring of X-linked proliferative syndrome carriers  The antigen chosen for vaccine development is the MA antigen gp 340/220 as antibodies against this antigen are virus neutralizing  This vaccine is being tried in Africa

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HHV-6 and HHV-7: ubiquitous, found worldwide Transmitted mainly through contact with saliva and through breast feeding HHV-6 and HHV-7 infections are acquired rapidly after the age of 4 months when the effect of maternal antibody wears off Adulthood, 90-99% of the population had been infected by both viruses HHv-6 and HHV-7 remains latent in the body after primary infection and reactivates from time to time

CLINICAL MANIFESTATIONS:  Primary HHV-6 infection: associated with Roseola infantum  Infants: 4 months and 2 years  A spiking fever develops over a period of 2 days followed by a mild rash. The fever is high enough to cause febrile convulsions.  May be complicated by encephalitis  If primary infection is delayed until adulthood, there is a small chance that an IM-like disease may develop in a similar manner to EBV and CMV  NO firm evidence linking HHV-6 to lymphomas or lymphoproliferative diseases  NO firm disease association with HHV-7 at present  Although both viruses may be reactivated in Immunocompromised patients, it is yet uncertain whether they cause significant disease since CMV is almost invariably present DIAGNOSIS AND MANAGEMENT:  Roseola infantum: clinical  Very few virology laboratories offer a diagnostic service for HHV-6 or HHV-7 infection  Virus isolation: complicated  Serology: mainstay of diagnosis – specific IgM and IgG are detected  NO specific antiviral treatment HUMAN HERPES VIRUS 8  Belong to the gammaherpesvirus subfamily  Originally isolated from cells of Kaposi’s sarcoma (KS)  Associated wit KS as well as some lesser known malignancies such as Castleman’s disease and primary effusion lymphomas  HHV-8 DNA is found in almost 100% of cases of Kaposi’s sarcoma  Most patients with KS have antibodies against HHV-8  Seroprevalence of HHV-8: low among general population but is high in groups of individuals susceptible to KS, such as homosexual  Does not have a ubiquitous distribution

OTHER HUMAN HERPES VIRUSES PROPERTIES OF HHV-6 AND 7:  Belong to the betaherpesvirus subfamily of herpesviruses  Double stranded DNA genome of 170 kbp  Main target cell: T-lymphocyte, although Blymphocytes may also be infected  HHV-6 and HHV-7 share limited nucleotide homology and antigenic cross-reactivity  It is thought that HHV-6 and HHV-7 are related to each other in a similar manner to HSV-1 and HSV2 EPIDEMIOLOGY AND PATHOGENESIS: 6of 6