Herpesviruses Herpes simplex I & II (cold sores, genital herpes) D- virology Herpesviruses Herpes simplex I & II (cold sores, genital herpes) Varicella zoster (chicken pox, shingles) Cytomegalovirus (microcephaly, infectious mono) Epstein-Barr virus (mononucleosis, Burkitt’s lymphoma) Human herpesvirus 6 & 7 (Roseola) Human herpesvirus 8 (Kaposi’s sarcoma)

Cold Sores

Zoster

Roseola

Human Herpesviruses Virus Subfamily Disease Site of Latency Herpes Simplex Virus I α Orofacial lesions Sensory Nerve Ganglia Herpes Simplex Virus II α Genital lesions Sensory Nerve Ganglia Varicella Zoster Virus α Chicken Pox Sensory Nerve Ganglia Recurs as Shingles Cytomegalovirus β Microcephaly/Mono Lymphocytes Human Herpesvirus 6 β Roseola Infantum CD4 T cells Human Herpesvirus 7 β Roseola Infantum CD4T cells Epstein-Barr Virus γ Infectious Mono B lymphocytes, salivary Human Herpesvirus 8 γ Kaposi’s Sarcoma Kaposi’s Sarcoma Tissue

Herpes Simplex Virus Prototype of group

Virion stabiliy Enveloped virus Sensitive to dessication Easily inactivated by detergents and lipid solvents

Virion structure Enveloped, spherical virion Icsoahedral capsid 120 - 200 nm >12 virally encoded glycoproteins Tegument proteins

Genome structure Linear double-stranded DNA 120 - 230 kb Genetic complexity -- isomers

Genome structure Linear double-stranded DNA 120 - 230 kb Genetic complexity # of genes

Replication Penetration by fusion with plasma membrane Nuclear site of replication 80 or so viral proteins are expressed in regulated fashion: IE - immediate early E - Early L - Late Capsids assemble in nucleus and bud through nuclear membrame

Life-long Latency

Three manifestations of HSV latency Key Feature: there is a wide spectrum of clinical presentations Some individuals (5 - 10%) have frequent clinical reactivation Most individuals reactivation is clinically asymptomatic In ALL cases, virus is shed

Transmission of HSV-1 and HSV-2 Skin to skin contact The virus does not penetrate intact skin Mild abrasion or chapping of skin can allow infection

Tissue tropism of HSV-1 and HSV-2 Causes 95% of orofacial herpes (remainder caused by HSV-2) Causes 10 - 30% of primary genital herpes (but seldom recurs there) HSV-2: Causes primary and recurrent genital herpes infections May cause primary oral herpes but, like HSV-1 in genital area, it seldom recurs there

Eczema/Herpes

Herpes Simplex Virus type 2 Infects the genital tract Is sexually transmitted Complicates childbirth

Diagnosis of Herpes Simplex Virus Infections: Viral Culture Tzanck prep Culture with monoclonal antibody staining Serology Polymerase chain reaction (PCR)

Spectrum of HSV recurrence Asymptomatic shedding Shedding with clinically apparent lesions

A study of HSV-2 recurrence in women

Asymptomatic Shedding of HSV Occurs in both HSV-1 and HSV-2 The only form of shedding in 1/2 to 2/3 of infected patients Involves low amounts of virus Accounts for most transmissions to infected contacts and neonates Is not completely suppressed by acyclovir

2/3

2/3 of the acquisitions of genital herpes come from clinically asymptomatic partners

Alpha Herpesviruses Site of Latency Herpes Simplex Virus type 1 Sensory neurons Herpes Simplex Virus type 2 Sensory neurons Varicella Zoster Virus Sensory neurons Beta Herpesviruses Cytomegalovirus Lymphocytes Human Herpesvirus 6 CD4 T cells Human Herpesvirus 7 CD4 T cells Gamma Herpesviruses Epstein-Barr Virus B lymphocytes Human Herpesvirus 8 Sarcoma tissue

Two Unique Features of VZV: Airborne spread or skin to skin contact More severe infection if primary infection occurs as an adult

Complications of Varicella Reye’s Syndrome Bacterial Superinfection of lesions (more common in younger patients) Varicella pneumonia Neonatal varicella -- disseminated, 30% mortality

Varicella Pneumonia Age Fatalities per 100,000 <1 6.23 1 - 14 0.75 <1 6.23 1 - 14 0.75 15 - 19 2.70 30 - 49 25.20

Varicella patients at risk ADULTS PREGNANCY (3rd trimester) IMMUNOCOMPROMISED The mortality rate for varicella pneumonia in leukemic children receiving chemotherapy is 1,000 times higher than in healthy children. Note: Children with isolated agammaglobulinemia are not at risk!

Neonatal Varicella

Zoster

Varicella Vaccine Prevents 40 - 70% of chickenpox occurrence Greatly reduces the severity in the rest Attenuated virus Can still establish latency and reactivate Question: How long will immunity last?

Complications of Zoster Postherpetic Neuraligia Affects 25 - 50% of zoster patients over 50 Pain may persist for months or even years

Alpha Herpesviruses Site of Latency Herpes Simplex Virus type 1 Sensory neurons Herpes Simplex Virus type 2 Sensory neurons Varicella Zoster Virus Sensory neurons Beta Herpesviruses Cytomegalovirus Lymphocytes Human Herpesvirus 6 CD4 T cells Human Herpesvirus 7 CD4 T cells Gamma Herpesviruses Epstein-Barr Virus B lymphocytes Human Herpesvirus 8 Sarcoma tissue

Transmission of CMV In utero Early childhood (saliva, etc.) Venereal in young adults Blood transfusion Organ transplantation

Clinical Manifestations of CMV Normal Host: Asymptomatic in the majority of cases Infectious mononucleosis Congenital CMV: Primary CMV infection in 3rd trimester of pregnancy of a seronegative mother Immunocompromised: Pneumonitis in bone marrow transplants Retinitis in AIDS patients

Alpha Herpesviruses Site of Latency Herpes Simplex Virus type 1 Sensory neurons Herpes Simplex Virus type 2 Sensory neurons Varicella Zoster Virus Sensory neurons Beta Herpesviruses Cytomegalovirus Lymphocytes Human Herpesvirus 6 CD4 T cells Human Herpesvirus 7 CD4 T cells Gamma Herpesviruses Epstein-Barr Virus B lymphocytes Human Herpesvirus 8 Sarcoma tissue

EBV Mono

EBV mononucleosis

Heterophile Antibody (IM) EBV induces many cellular proteins An antibody against one of these new celular proteins is able to agglutinate sheep red blood cells EBV monucleosis is heterophile antibody positive CMV mono is heterophile antibody negative

IM Serology VCA IgM rises and falls early in infection VCA IgG antibodies persist EBV mononucleosis is heterophile antibody positive CMV mononucleosis is heterophile antibody negative; no antibodies to VCA of EBV

Antiviral therapy

Acyclovir Ganciclovir Deoxyguanosine Deoxyadenosine Ribavirin Vidarabine