Sequential Steps in Viral Infection Entry Spread Shedding Transmission Propagation Three Problems Viruses must solve: Reproduction Spread Evasion of Host Defenses Viral pathogenesis is the result of viral strategies designed to overcome these problems

Entry Skin/Mucous Membranes Transcutaneous Injection Urogenital Tract Oropharynx and GI Tract Respiratory Tract

Entry Skin/Mucous membranes Invasion of intact skin unlikely Stratum corneum is keratinized, no live cells Break in skin allows viral access to specific underlying cells Herpes Simplex Virus and pox viruses can replicate in germinal cells in epidermis and fibroblasts and macrophages in the dermis Papillomaviruses (causes cervical warts and cancer) infect germinal cells of the epidermis but complete life cycle only in the more superficial stratum granulosum

(Acute Hemorrhagic Conjunctivitis) Entry Skin/Mucous membranes Conjunctiva of the eye; a specialized mucous membrane Certain adenovirus serotypes Coxsackie virus A24 Enterovirus 70 Herpes Simplex Virus Herpes Zoster Virus infection can cause severe conjuncvititis Picornaviruses (Acute Hemorrhagic Conjunctivitis)

Entry Transcutaneous Injection Arboviruses (Insect borne) Virus life cycle must alternate between insect vector and vertebrate host (e.g. West Nile Virus, Dengue Virus) Virus is injected when the insect takes a blood meal Symptomalogy can differ widely: non-symptomatic to fatal encephalitis for West Nile, and slight febrile illness to fatal hemorrhagic fever for dengue Bite of infected animal (Rabies) Intramuscular innoculation with virus-contaminated saliva Virus has pre-dilection for the limbic system; produces personality changes IV innoculation HIV Hepatitis C

Entry Urogenital Tract (Sexually Transmitted) Puncture wound from needle used to culture genital herpes Urogenital Tract (Sexually Transmitted) Infects/replicates in epithelial cells Herpes Simplex Virus-2 (herpes) Papillomaviruses (warts, cervical cancer) Transmucosal infection Hepatitis B Access circulation via surface capillaries that supply mucous membranes HIV textbook is not entirely correct; HIV is probably “ferried” to lymphoid organs to infect CD4+ T-cells by dendritic cells that reside in the submucosa Condyloma acuminatum (HPV-6)

DC-SIGN: A Conduit for Transfer of HIV to Lymphoid Organs? Geijtenbeek, T.B.H. et al, Cell 100: 594

Entry Oropharynx and Gastointestinal Tract ReoVirus

Entry Respiratory Tract Hanta Virus (Sin Nombre Virus)

Spread HIV in semen: Local Spread Dissemination --Cell free virus vs cell-associated virus --consequences for prophylactic treatment

Poliovirus Viremia Viremia decreases with onset of antibody response

Virus Spread from Blood to Tissues Some Paramyxovirus (causes vasculitis) (e.g. Mumps) (“Trojan Horse” e.g. HIV)

Shedding GI Tract Feces Epithelial Cells (Reovirus) Liver--->Bile---->Bile duct (Hepatitis A) Poliovirus Respiratory Tract (Rhinovirus, Influenza) Aerosols, pharyngeal secretions Skin Papillomavirus (Warts) Pox viruses (smallpox) Mucous Membranes (Oral/Genital fluids) HSV-1 (oral), HSV-2 (genital) Epstein Barr Virus (mononucleosis--kissing disease in college kids) Rabies (saliva) HBV, HIV (semen) Blood, Urine, Milk HBV, HIV, HCV, CMV (persistent viremia)

Enviromental Survival of Shed Virus Transmission depends Amount of shedding Duration of Shedding Survival time in environment HIV not infectious after drying Poliovirus sensitive to low humidity Decrease transmission during Winter Transmission all year in tropical climates GI Environment (acid inactivates most viruses) Hep A, B, C, D, E all replicate in liver and are secreted in bile but only Hep. A and E are transmitted by fecal-oral route

1918 flu pandemic killed 40 million people in 5 months (~ same # killed by HIV in the last 20 years)

Transmission/Propagation Acute Infections Requires minimal population threshold Transmissibility, Ro>1 E.g. Measles will eventually disappear if isolated population <500,000 Ab prevalence may provide an indicator of transmissibility; age and population-specific incidence Cases per 100 population % with Antibody

Transmission/Propagation Persistent Infections Can persist in small populations HIV, HBV, VZV

Control and Eradication Effective vaccines can eradicate viral infections that result in acute infections in relatively short periods of time Smallpox, Polio(?) Persistent infections will take generations to disappear, even with effective vaccines