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 • 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 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: • 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) • Merkel cell polyoma virus (MCV, MCpV) • 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