Minding Herpes and Cues

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Minding herpes and cues

Robert Siegel Human Health and Disease Monday, October 11, 2010

Robert Siegel Herpesvirus

“Creeping”

Robert Siegel Herpesviruses

Classification

- double standed DNA viruses - large, nonsegmented genome - icosahedral nucleocapsid, enveloped

Robert Siegel Virus Classification

DNA viruses

Double stranded Double stranded Single stranded Partially double stranded enveloped naked

Pox Adeno Parvo Hepadna Herpes Papilloma Anello (Mimi) Polyoma (Circo) Virus Classification

DNA viruses

Double stranded Double stranded Single stranded Partially double stranded enveloped naked

Pox Adeno Parvo Hepadna Herpes Papilloma Anello (Mimi) Polyoma (Circo)

HSV 1 and 2 VZV EBV CMV HHV6 and 7 HHV-8 (KSHV) (Herpes B – simian zoonosis)

Virology MAJOR FACTORS USED IN DIFFERENTIATING HUMAN VIRAL FAMILIES

• Type of nucleic acid (DNA vs RNA) • Nucleic acid strandedness (ds, ss, partially ds) • “Sense” of ss nucleic acid (-, +, ambisense) • Capsid morphology icosahedral, helical, complex • Envelope (present or absent) • Electron micrographic (EM) appearance • Genome segmentation • Size of virion and/or genome • Nature of gene expression (e.g. nature and number of mRNA transcripts)

Robert Siegel Virology MAJOR FACTORS USED IN DIFFERENTIATING HUMAN VIRAL FAMILIES

• Type of nucleic acid (DNA vs RNA) • Nucleic acid strandedness (ds, ss, partially ds) • “Sense” of ss nucleic acid (-, +, ambisense) • Capsid morphology icosahedral, helical, complex • Envelope (present or absent) • Electron micrographic (EM) appearance (fried egg) • Genome segmentation (number of segments = 1) • Size of virion and/or genome (big and big) • Nature of gene expression (3 kinetic classes) (e.g. nature and number of mRNA transcripts) Robert Siegel Herpesviruses

Viral morphology

- fried-egg EM appearance - virion structure (envelope, tegument, capsid, core)

Robert Siegel

The Eight Human HERPESVIRSUS Virology

• Herpes simplex virus 1 (HSV-1) • Herpes simplex virus 2 (HSV-2) • Varicella-zoster virus (VZV) • Epstein-Barr virus (EBV) • Cytomegalovirus (CMV) • Human herpes virus 6 (HHV-6A and B) • Human herpes virus 7 (HHV-7) • Human herpes virus 8 (HHV-8, KSHV) Robert Siegel Hallmarks of Human HERPESVIRUS Infection Virology

• Incurability • Latency • Reactivation • Ubiquity • Multiple clinical manifestations • Silent infection • Opportunistic infection

Robert Siegel Hallmarks of Human HERPESVIRUS Infection Virology

• Incurability • Latency • Reactivation • Ubiquity • Multiple clinical manifestations • Opportunistic infection • Silent infection

Robert Siegel Hallmarks of Human HERPESVIRUS Infection Virology

• Incurability • Latency • Reactivation • Ubiquity • Multiple clinical manifestations • Opportunistic infection • Silent infection

Robert Siegel Etymology

A word about latency

• Viral latency • Replication cycle latency • Clinical latency

Robert Siegel Hallmarks of Human HERPESVIRUS Infection Virology

• Incurability • Latency • Reactivation • Ubiquity • Multiple clinical manifestations • Silent infection • Opportunistic infection

Robert Siegel HSV

Nomenclature

• First episode primary infection

• First episode nonprimary infection

• Recurrent infection

• Asymptomatic infection

• Asymptomatic shedding

Robert Siegel

Immunology Causes of SEVERE IMMUNODEFICIENCY:

• Genetic deficiency (inherited) • Drug induced • Cancer induced • Retroviral infection

Robert Siegel Immunology DRUG INDUCED IMMUNODEFICIENCY:

• Transplantation • Cancer Chemotherapy • Suppression of Immunological Excess

Robert Siegel Immunology Causes of SEVERE IMMUNODEFICIENCY:

• Genetic deficiency (inherited) • Drug induced • Cancer induced • Retroviral infection

Robert Siegel Immunology Additional causes of SEVERE IMMUNODEFICIENCY:

• Viral and other infections • Malnutrition • Physiological stress • Psychological factors

Robert Siegel Herpesvirus

Of cold sores and fever blisters

Robert Siegel Immunology Additional causes of SEVERE IMMUNODEFICIENCY:

• Viral and other infections • Malnutrition • Physiological stress • Psychological factors

Robert Siegel Herpesvirus

All of these are signals for reactivation

Robert Siegel Hallmarks of Human HERPESVIRUS Infection Virology

• Incurability • Latency • Reactivation • Ubiquity • Multiple clinical manifestations • Silent infection • Opportunistic infection

Robert Siegel The Eight Human HERPESVIRSUS Virology

• Incurability • Latency • Reactivation • Ubiquity • Multiple clinical manifestations • Silent infection • Opportunistic infection

Robert Siegel Herpes simplex infection Clinical manifestations

• herpes labialis stomatitis, gingivostomatitis (cold sore, fever blister) • herpes genitalis • herpes simplex virus pharyngitis • herpes keratitis, keratoconjunctivitis • herpetic whitlow • eczema herpeticum = Kaposi's varicelliform eruption • herpes encephalitis • herpes neonatorum • disseminated herpes simplex

Robert Siegel Hallmarks of Human HERPESVIRUS Infection Virology

• Incurability • Latency • Reactivation • Ubiquity • Multiple clinical manifestations • Silent infection • Opportunistic infection

Robert Siegel Herpesvirus

From chickenpox to CMV

Robert Siegel Hallmarks of Human HERPESVIRUS Infection Virology

• Incurability • Latency • Reactivation • Ubiquity • Multiple clinical manifestations • Silent infection • Opportunistic infection

Robert Siegel Hallmarks of Human HERPESVIRUS Infection Virology

• Incurability • Latency • Reactivation • Ubiquity • Multiple clinical manifestations • Silent infection • Opportunistic infection

• (oncogenicity) Robert Siegel Human herpes form a group A creepy ignominious troop Distinctive hallmarks separate This noisome little gang of eight

Reactivation - coming out Ubiquity, they’re all about Latency is on the list Both inapparent, and opportunist

Add incurability Herpes for eternity Oncogenic potential too But so far shown for just a few. RDS Robert Siegel 11/14/05 Virology Viruses associated with HUMAN CANCER:

• Human T-cell lymphotropic virus type I (HTLV-1) • Epstein-Barr virus (EBV) • Human papilloma virus (HPV) • Hepatitis B virus (HBV) • Hepatitis C virus (HCV) • Kaposi’s sarcoma associated herpes (KSHV)

Robert Siegel Virology Viruses associated with HUMAN CANCER:

• Xenotropic murine retrovirus (XMRV) Robert Siegel

Herpesvirus

Of nuns and prostitutes

Robert Siegel Herpesvirus

Of correlation and causality

Robert Siegel The Eight Human HERPESVIRSUS Virology

• Herpes simplex virus 1 (HSV-1) • Herpes simplex virus 2 (HSV-2) • Varicella-zoster virus (VZV) • Epstein-Barr virus (EBV) • Cytomegalovirus (CMV) • Human herpes virus 6 (HHV-6) • Human herpes virus 7 (HHV-7) • Human herpes virus 8 (HHV-8, KSHV) Robert Siegel Viral exanthems

Classification

• Erythematous maculo-papular • Vesicular • Nonerythematous papular • Other (petechial, pustular, etc.)

Robert Siegel

Vesicular Viral Exanthems: Common Themes

• Fluid-filled lesions contain infectious virus • Highly contagious

Robert Siegel

Vesicular Viral Exanthems: Common Taxonomic Themes

Large DNA viruses

Robert Siegel HSV

Clinical

• Incubation period 5-7 days (range 2-12 days)

• In general, HSV-1 results in clinical manifestations “above the belt”

• In general, HSV-2 results in clinical manifestations “below the belt”.

• These generalizations are violated around 5-15% of the time.

• This is said to be due to “mixing and matching of mucous membranes”

• However, there are differences in tropism.

Robert Siegel

COMPARISON OF HSV-1 AND HSV-2

HSV-1 HSV-2

Nongenital Location Genital Nongenital Transmission Genital 67 DNA (Moles/100 cc 69 Small Lesion Size Larger HSV

Transmission

• Highly infectious via apposition of skin, mucous membranes, or secretions • May spread from visible lesions or as a result of asymptomatic shedding • Spread enhanced if skin is damaged (e.g. burns, eczema, diaper rash)

C. Prober HSV

Transmission

• Perinatal transmission occurs at high frequency among parturient women with primary infection. • Recurrent disease may be perinatally transmitted at a much lower frequency. • Intrauterine transmission has also been documented at a very low rate.

Robert Siegel HSV Epidemiology

• Majority of infections are asymptomatic or atypical • HSV-1 infections begin in infancy and continue throughout life • HSV-2 infections begin with onset of sexual activity and continue throughout life • Worldwide distribution with humans as the only reservoir • Spread enhanced if skin is damaged (e.g. burns, eczema, diaper rash)

C. Prober Herpesvirus

Latency

Robert Siegel HSV

Pathophysiology

• Infection following exposure of abraded skin or mucosal surfaces • Penetration of epidermal, dermal, and mucosal epithelial cells • Uptake by cutaneous neurons • Migration to sensory ganglia • Synthesis of infectious virus • Return to inoculation site via peripheral sensory nerves • Destruction of epithelial cells and lesion formation • Establishment of latency in sensory ganglia • Maintenance of latency with periodic reactivation C. Prober

HSV

Epidemiology

• Latency follows all HSV infections, contributing to the ever increasing infectious “pool”

• Approximately 40-90% of children and adolescents are seropositive for HSV-1

• Approximately 15-30% of young adults are seropositive for HSV-2

• Prevalence rates are affected by geographic location, socioeconomic status, race, and age

C. Prober HSV

Pathology

• Infected cells swell, degenerate, and form multinucleated giant cells with intranuclear inclusions

• Local inflammation

• Vesicle formation, if mucocutaneous site

C. Prober Herpes simplex in the suprapubic area John L. Bezzant,M.D. Note the grouped blisters, and the patient experienced severe pain. This was a medical student and he was concerned about the sexual partner from whom he may have contracted this. (His sexual partner was a woman). Epidermis being destroyed by herpes virus infection John L. Bezzant,M.D. Epidermis being destroyed by herpes virus infection. The herpes virus causes essentially complete destruction of the epidermis, and what is seen clinically is a blister, the top of which is formed largely by the very thin stratum corneum. Herpesvirus

Mixing and matching of mucus membranes

Robert Siegel Herpesvirus

HSV-1

Robert Siegel

Keratitis caused by herpes simplex virus Herpesvirus

whitlow

Robert Siegel

HSV encephalitis

HERPESVIRUS HOMINIS GENITAL INFECTION Clinical Case Study

CC: Rash and fever. HPI: CC: Fever, headache and vaginal pain.

History: A nineteen-year-old woman who has recently become sexually active has developed fever, headaches and some dysuria and vulvar pain for the last two days.

Robert Siegel Clinical Case Study

PE: Temp = 38.8°C Resp rate = 14 Heart rate = 90 Blood pressure = 100/70

Robert Siegel Clinical Case Study

PE continued: Positive findings include slight neck stiffness, bilateral tender inguinal lymphadenopathy, and multiple bilateral tender erosions in the vulvar area with few vesicles. The rest of the systemic exam is normal. Labs/radiography: none ordered

Robert Siegel G.O.P.

HSV

Epidemiology

• An estimated 50 million American have genital herpes infection.

Robert Siegel HSV

Transmission

• Most shedding is asymptomatic.

• Most transmission is due to asymptomatic shedding.

• First reactivation may be temporally distant to time of initial infection.

C. Prober Up to 70% of Transmission May Occur During Asymptomatic Viral Shedding

• 9.7% of patients infected their partner (14/144) • Transmission frequently occurs between outbreaks

Transmission during asymptomatic viral shedding Up to 70% ~30%

Transmission during symptomatic outbreaks Mertz GJ, et al. Ann Intern Med. 1992;116:197-202. Neonatal HSV Infection Gravest consequence of gestational HSV Contracted from infected birth canal Risk greatest if maternal primary infection Maximum risk, < 4 weeks of age 3 forms; SEM, Disseminated, CNS 70% untreated mortality rate

Skin, Eye, Mucosal (SEM) Disease

40% of all cases Onset at 1-2 weeks of age Skin lesions and conjunctivitis Importance of rapid diagnosis (DFA) Culture skin lesions / eye discharge Progression if ignored

Disseminated Disease

25% of all cases Onset at < 1 week of age Sepsis, liver failure, respiratory distress Need for high index of suspicion Culture all sites Herpes viruses preferentially spread to the liver, lung, & brain.

Central Nervous System (CNS) Disease

35% of all cases Onset at 2-3 weeks of age Lethargy, irritability, fever, seizures Typical EEG CSF: culture & PCR

Neonatal HSV Infections:Therapy

Outcome depends upon disease type

Type of infection # treated %survival %intact

SEM 85 100% 94% CNS 71 86% 36% Disseminated 46 54% 59%

N Engl J Med 1991;324:444 HSV

Immunity

• Brisk immune response following primary infection

• Antibody reflects prior infection not protection

• Important T-cell factors incompletely defined

C. Prober HSV

Diagnosis

• Tzanck prep (fast, easy, cheap, sensitive) • Antibody seropositive: EIA, LA, etc. (limited utility in determining recent or active infection) • Immunofluorescence • Viral culture – rapid growth, typical CPE • PCR N.B. - Type specific assays based on gG have been developed.

Robert Siegel

Tzanck prep John L. Bezzant,M.D. For a Tzanck prep, the base of the blister is scraped and it is smeared on the slide.

Tzanck prep John L. Bezzant,M.D. The slide is not heated because it would distort the cellular morphology and make it virtually impossible to read the slide. The modified right stain kits come with instructions.

Magnification identifies multinucleated cells John L. Bezzant,M.D. Moderate magnification can be used to identify possible multinucleated giant cells

Multinucleated giant cells John L. Bezzant,M.D. Multinucleated giant cells are very large epidermis cells that have multiple nuclei. Multinucleated giant cells with HSV cervicitis

Diagnosis of HSV Infections

Direct examination for virus: DFA Herpesvirus

Therapy

Robert Siegel HSV

Treatment

• A number of nonpharmacologic interventions for the treatment of recurrent HSV have been suggested. • Placebo effects may produce significant improvement

Robert Siegel HSV

Treatment

• Effective antivirals are available for the treatment and suppression of clinical disease

• Currently licensed antiherpetic drugs are predominant nucleoside analogs that inhibit viral replication by incorporation into the growing nucleotide chain followed by chain termination

Robert Siegel

Molecular biology

Nucleoside analogs • Antivirals • Cancer chemotherapeutics • DNA sequencing

Robert Siegel Treatment Therapeutic index The ratio of the ED50 of a drug to produce a toxic effect to the ED50 to produce a therapeutic effect.

Suppression of lesions

Robert Siegel

HSV

Treatment

Pharmacologic agents used in the treatment of HSV • Acyclovir • Famcyclovir • Valacyclovir • Idoxuridine (ophthalmic) • Trifluridine (ophthalmic) • Vidarabine (Ara-A, cytosine arabinoside – CNS disease)

Robert Siegel

Reduction in the Risk of Transmission

TREAT HIM

PROTECT HER

Please consult complete Prescribing Information for VALTREX. HSV

Prevention

• Barrier methods are very important in reducing transmission. • Ceasarian section decreases transmission to the newborn in primary infections of the mom. • Acyclovir is used for secondary prevention.

Robert Siegel HSV

Vaccination

• There is no currently licensed vaccine for HSV-1 or HSV-2. • There are numerous of vaccine candidates currently under investigation. • A number of vaccines have reached human clinical trials. • A number of vaccine candidates focus on envelope glycoprotein gG. • DNA vaccines are a promising line of investigation.

Robert Siegel HSV

Vaccination

• gD2 subunit with AS04 adjuvant; GSK/NIH; in Phase III

• live attenuated ICP8 DISC virus vaccine; Xenova; Phase I/II

• other live attenuated, replication-competent virus vaccines; Avant (Phase I); AuRix (Phase II)

Robert Siegel

VZV (varicella-zoster virus)

Going down the zoster roster

Robert Siegel The Eight Human HERPESVIRSUS Virology

• Family: Herpesviridae • Subfamily: Alphaherpesvirus • Agent: Varicella Zoster Virus (VZV) • ICD-10 B01-B02 (ICD-9 052-053) • Reservoir: humans

Robert Siegel

Pox terminology

• Pox • Smallpox • Great pox • Chickenpox

Robert Siegel VZV terminology

• Chickenpox • Varicella • Shingles • Zoster

Robert Siegel Virology MAJOR ROUTES OF VIRAL TRANSMISSION

• RESPIRATORY • FECAL-ORAL • DIRECT CONTACT • SEXUAL • PARENTERAL • ARBO (arthropod-borne) • VERTICAL (Intrauterine, Perinatal, Breast Milk) • FOMITE

Robert Siegel VZV

Transmission

• Respiratory droplets

• Highly contagious

Robert Siegel VZV

Epidemiology

• Young children

Robert Siegel VZV

Epidemiology

• Young children

• Highly seasonal

Robert Siegel

VZV

Epidemiology

• Young children

• Highly seasonal

• Highly species specific

Robert Siegel VZV Pathogenesis

• Respiratory transmission

• Initial replication in oral pharynx

• Hematologic dissemination

• Development of acute disease

• Latency in sensory ganglia

• Reactivation

Robert Siegel

VZV Pathology

• Characteristic CPE

• Viral inclusion bodies (nuclear)

• Multinucleated giant cells

• Vesicular lesions are filled with virus

Robert Siegel

Clinical features

Chickenpox Primary infection

Robert Siegel Viral exanthems

Classification

• Erythematous maculo-papular • Vesicular • Nonerythematous papular • Other (petechial, pustular, etc.)

Robert Siegel VZV

Clinical features

• Highly contagious

• Low pathogenicity

• Successive waves of lesions

• More severe in adults

Robert Siegel

Herpesvirus

Complications • Scarring

Robert Siegel Herpesvirus

Complications • Scarring Early lesions? Secondary infection? Stochastic?

Robert Siegel

Herpesvirus

Complications • Scarring • Reactivation

Robert Siegel Herpesvirus

Zoster

Robert Siegel

Herpesvirus

Complications • Scarring • Reactivation  post herpetic neuralgia

Robert Siegel Herpesvirus

Complications • Scarring • Reactivation • Varicella pneumonia

Robert Siegel

Herpesvirus

Complications • Scarring • Reactivation • Varicella pneumonia  Most severe in pregnant women

Robert Siegel

Complications of VZV infection - I

• Varicella pneumonia (esp in pregnancy) • Encephalitis • Bacterial super infection (including necrotizing fasciitis) • Aseptic meningitis • Myocarditis

Robert Siegel

Complications of VZV infection - II

• Glomerulonephritis • Purpura fulminans • Reye’s syndrome • Transverse myelitis • Congenital malformation

Robert Siegel Herpesvirus

Complications • Scarring • Reactivation • Varicella pneumonia • Reyes syndrome

Robert Siegel Reye’s syndrome • Hepatoencephalopathy • Sudden onset, vomiting, lethargy • Pediatric generally 5-16 • Associated with VZV and influenza in convalescent period • High mortality (20-30%) • High morbidity (60% permanent neurological or psychological damage) • Rare • Increased risk with use of salicylates

Herpesvirus

Complications • Scarring • Reactivation • Varicella pneumonia • Reyes syndrome • Secondary infection Robert Siegel VZV

Treatment

Pharmacologic agents used in the treatment of VZV • Acyclovir • Famcyclovir • Valacyclovir

Robert Siegel Prevention of Viral Disease

Medical • Active immunoprophylaxis - vaccination • Passive immunoprophylaxis - antibody administration • Prophylatic antiviral medication

Robert Siegel Herpesvirus

Vaccination

Robert Siegel

Vaccination

Varicella zoster virus

Varivax • Live, attenuated

• Oka strain

• Licensed 1995

• Merck

Robert Siegel Attenuateda Host range mutantb Temperature sensitive mutant Cold adapted mutant Deletion mutant Live Recombinantc

Virulentd

Virion

Anti-idiotype Inactivated Purified Synthetic Proteine “Cloned”f

Varicella zoster virus

Zostavax Vaccine now approved for suppression of shingles

Robert Siegel Varicella zoster virus

VZIG

Robert Siegel The Eight Human HERPESVIRSUS Virology

• Herpes simplex virus 1 (HSV-1) • Herpes simplex virus 2 (HSV-2) • Varicella-zoster virus (VZV) • Epstein-Barr virus (EBV) • Cytomegalovirus (CMV) • Human herpes virus 6 (HHV-6a, HHV-6b) • Human herpes virus 7 (HHV-7) • Human herpes virus 8 (HHV-8, KSHV) Robert Siegel •

HHV6a, HHV6b, HHV7 Herpesvirus

• Family: Herpesviridae • Subfamily: Betaherpesvirinae

• Genus: Roseolovirus (3) • Agents: HHV-6a, HHV-6b, HHV-7 • ICD-10 B08.2 (ICD-9 057.8) • Reservoir: humans • Infect CD4+ T-cells

Robert Siegel •

HHV-6a, HHV-6b, HHV-7 Clinical

Disease associations • Roseola (HHV-6b, HHV-7) • Synonyms: Roseola subitum, Roseola infantum, Exanthem subitum, Sixth disease

Robert Siegel Herpesvirus

Roseola

Robert Siegel FILATOV CLASSIFICATION Viral Exanthems

RED RASHES OF CHILDHOOD

1) MEASLES (paramyxovirus: rubeola) 2) SCARLATINA (bacteria: streptococcus) 3) RUBELLA (togavirus: rubella) 4) SCARLATINOID (???) 5) ERYTHEMA INFECTIOSUM (parvovirus: B-19) 6) ROSEOLA SUBITIUM (herpesvirus: HHV-6)

Robert Siegel FILATOV CLASSIFICATION Viral Exanthems

VIRAL RED RASHES OF CHILDHOOD

1) MEASLES (paramyxovirus: rubeola) 2) RUBELLA (togavirus: rubella) 3) ERYTHEMA INFECTIOSUM (parvovirus: B-19) 4) ROSEOLA SUBITIUM (herpesvirus: HHV-6) 5) ENTEROVIRAL RASHES (picornavirus: enteroviruses)

Robert Siegel

Erythematous Viral Exanthems: Common Themes

• Lesions generally do not contain virus • Rash is immunological response • Viremic phase • Period of maximal infectivity usually precedes rash. • Enduring immunity • Prevalence in childhood

Robert Siegel Roseola Clinical

• Incubation period 10 days (range 5-15) slightly longer in transplant recipients • Acute febrile illness • Very high fever - as high as 41oC (106oF) • Association with febrile seizures • Duration of fever: 3-5 days • Evanescent maculopapular exanthem in post-febrile phase

Robert Siegel Roseola Epidemiology

• World-wide distribution • Peak incidence: 6-12 months of age • Most children are seropositive by age 2

Robert Siegel Roseola Transmission

• Asymptomatic shedding from the salivary glands may occur throughout life • Contact with saliva is believed to be an important route of transmission • Virus may be transmitted by kidney or liver transplantation

Robert Siegel

Roseola Management

• There are no licensed treatments. • There are no licensed vaccines or promising vaccine candidates

Robert Siegel Recurrent Aphthous Ulcers (RAU) Clinical Etiology unknown

Robert Siegel The hypothesisThe ofhypothesis Drs. Robert of Drs.D. Siegel Robert D. Siegel and Reubenand Granich Reuben that Granich recurrent that recurrent aphthous ulcersaphthous (RAU) ulcers are a (RAU)clinical are a clinical manifestationmanifestation of human herpesvirus of human herpesvirus 6 6 (HHV6) reactivation(HHV6) reactivationis intriguing is and intriguing and should be tested.should be tested.

OralOral Surgery, Surgery, Oral Oral Medicine, Medicine, OralOral Pathology Pathology VolVol 76, 76, Number Number 4, 4, 406 406

Herpesviruses

KSHV

Robert Siegel The Eight Human HERPESVIRUS Virology

HHV-8 Etiology

• Family: Herpesviridae • Subfamily: Gammaherpesvirinae

• Genus: Rhadinovirus (2) • Synonyms: Kaposi’s sarcoma associated herpesvirus, (KSHV) • Discovered in 1994 (Chang et al.) • Contain immune modulating proteins

Robert Siegel KSHV Historical

• Isolation by Chang and Moore (1994) • Representational difference analysis (RDA) • 2000 articles

Robert Siegel KSHV Epidemiology

• 33% homosexual males • 8% HIV neg patients attending STD clinics • 3% blood donors (HIV negative)

Robert Siegel KSHV Clinical Clinical disease associations: • Primary infection – none characterized • Secondary infection – none characterized • Oncogenic associations – KS and others • Most infections in immunocompetent individuals are asymptomatic

Robert Siegel Virology Viruses associated with HUMAN CANCER: • Human T-cell lymphotropic virus type I (HTLV-1) • Epstein-Barr virus (EBV) • Human papilloma virus (HPV) • Hepatitis B virus (HBV) • Hepatitis C virus (HCV) • Kaposi’s sarcoma associated herpes (KSHV)

Robert Siegel KSHV Clinical Oncogenic associations: • Kaposi’s sarcoma (KS) • Primary effusion lymphoma (PEL) – rare form of B- cell lymphoma • Multicentric Castleman’s disease (MCD) - plasma cell variant Non-oncogenic associations: • Primary pulmonary hypertension (2003) Robert Siegel •

Kaposi’s sarcoma Epidemiology

• HIV associated KS • African endemic KS • “Classic” Mediterranean KS • Post-transplant KS

Robert Siegel •

Kaposi’s sarcoma Epidemiology

• Reservoir: humans • Second leading cause of death in HIV infected individuals (U.S.)

Robert Siegel •

Kaposi’s sarcoma Pathology

• Endothelial tumors • Characteristic KS spindle cells • KSHV DNA detected in spindle cells as site of latent infection • KSHV association found in all forms of KS • Cofactors for progression: immunodeficiency, others (unknown)

Robert Siegel

•

Primary effusion lymphoma (PEL) Clinical

• Body cavity-based lymphoma • Rare form of B-cell lymphoma

Robert Siegel •

Plasma cell variant of multicentric Castleman’s disease (MCD) Clinical • Hyperplastic B-cell lymphoproliferative disorder • HIV associated

Robert Siegel The Eight Human HERPESVIRSUS Virology

Herpes B virus a zoonosis may result in a highly fatal meningoencephalitis

Robert Siegel B-virus Virology

Synonyms: • Cercopithecine herpes virus 1 • Simian B virus • Herpes simiae • B virus Taxonomy • Alphaherpesvirus • Closely related to HSV Robert Siegel

B-virus Epidemiology Direct contact with Old-World monkeys • Veterinarians • Researchers

Robert Siegel