Pathogenesis and Control of Viral Infections Chapter 30

Principles of Viral Diseases Pathogenesis is disease progression A pathogenic virus is one that causes disease Virulence refers to the degree of pathogenicity Ebola Zaire virus is highly virulent Herpesviruses are not Clinical spectrum Subclinical Invisible or subtle infection May or may not progress further (80% of WNV infections are subclinical) Clinical Visible onset of disease

Pathogenesis of Viral Diseases Steps of pathogenesis Entry and primary replication (acute infection) Portals of entry where first localized infections occur Varies with virus Viral spread and cell tropism Sites distant from entry where virus can replicate Viremia - the spread of virus through the blood Nervous system spread - rabies, herpesviruses Infections are usually organ or tissue specific Usually controlled by viral proteins that mediate attachment to cells Viruses encode proteins, including enzymes, that seize control of susceptible cells Cellular transcription factors often dictate susceptibility Measles - a respiratory disease

Pathogenesis of Viral Diseases Steps of pathogenesis (cont.) Cell injury and clinical illness Cellular pathology and death (e.g., exiting virus) Immune response to tissue injury (inflammation and cytotoxicity) exacerbates clinical manifestations Recovery from Infection (convalescence) For most viral diseases, virus is eliminated by the immune response and complete recovery occurs Others have persistent infections Chronic - virus is always detectable Latent - virus sequesters in a tissue with recrudescence (recurrent outbreaks) In some cases, long-term or permanent disabilities occur Muscle weakness from West Nile virus infection Neurological manifestations; Polio, measles, mumps Virus Shedding Shedding is the release of virus from either cells or the animal It is required for virus transmission Coughing, sneezing, diarrhea, hemorrhage, etc.

Prevention and Treatment of Viral Infections Antiviral chemotherapy Nucleoside analogs - interfere with polymerases Nucleotide analogs - interfere with polymerases Non-nucleotide inhibitors - bind to polymerase such that it is inactivated Protease inhibitors - bind to and inactivate viral proteases that are required for polypeptide cleavage into mature viral subunit proteins AZT T

Prevention and Treatment of Viral Infections Interferons (Table 30-7) Type I IFNα, IFNβ Likely derived from ancestral gene duplication event Synthesized and secreted by all virally-infected cells Bind to Type I IFN receptors on adjacent cells, alerting them to the infection Induces the expression of dozens of antiviral genes Type II IFNγ AKA - immune interferon No sequence similarity to type I IFNs Synthesized by T cells and natural killer (NK) cells Binds to Type II IFN receptors and induces expression of antiviral genes

Prevention and Treatment of Viral Infections Interferons (cont.) Virus mechanisms to counteract IFNs Disabling PKR When IFN binds to its receptor, several signal transduction events occur, including the expression of PKR protein kinase gene PKR protein is activated by double-stranded RNA (autophosphorylated) Phosphorylated PKR binds to and inactivates eukaryotic protein synthesis initiation factor-2 (EIF-2), thus inhibiting protein synthesis Some viruses have proteins that disable PKR, thus protein synthesis continues Many other viral proteins target this pathway Clinical Studies Interferons have been used to treat some viral diseases Most notable - hepatitis C infection

Prevention and Treatment of Viral Infections Viral Vaccines General principles Vaccines work by stimulating an adaptive immune response (e.g. antibodies, T cells) without causing disease In the event the virus is subsequently encountered, antibodies and cells are poised to engage it before clinical manifestations arise Should provide durable immunity (decades) Inactivated Vaccines Inactivated vaccines usually stimulate a strong antibody response, but a weaker T cell response They usually require several boosters for strong immunity For many viruses, inactivation is ineffectual for vaccination Live, attenuated vaccines Infectious virus with very low or no pathogenic properties More closely resembles real infection, thus promotes both strong antibody and T cell responses Requires fewer or no boosters compared to inactivated vaccines

Prevention and Treatment of Viral Infections Viral Vaccines (cont.) Proper use of vaccines Vaccinations are public health programs Each vaccination has a target coverage rate This rate varies with each vaccine, usually 80%-90% If the target is reached, the disease is usually sporadic or nonexistent Just under the target and small outbreaks occur Substantially under the target leads to epidemics Future of Vaccines Genetically-modified hybrid vaccines Protein subunit vaccines Recombinant DNA Synthetic viral peptides Edible vaccines DNA vaccines Portal vaccines