Virulence Myxoma Virus (pox virus): -Used to attempt eradication of wild rabbits in Australia. -Natural Host = South American “rabbit” -In natural host, lesions form but host doesn’t (usually) die -Lethal to European rabbits (death in <10 days) -In Australia, Myxoma virus released and rabbit population assessed: -Resistant rabbits are selected for -Less virulent (attenuated) virus is selected for

Discovery and History of viruses Field of virology approx. 100 yrs Viruses may infect all organisms Viruses are an important selection pressure in the environment -Immune system evolution largely due to viruses and vica versa -eg TNF-receptor and IFN-gamma-receptor on viruses. -These genes acquired from hosts Viruses initially studied due to association with disease –in part because have to "see effect" of virus (before knew structure) –disease aspect still very important Influenza million died in pandemics ~ AIDS Now official pandemic Vaccines no that useful for pandemics -Problems are production and distribution, especially to 3rd-world countries.

Rotavirus, infant diarrhea – *Problem in 3 rd world countries* -Can’t replenish fluids without hospitals >600,000 deaths world wide /yr Smallpox, now eradicated - Virus held only by American and Russian CDC As late as 1950, epidemic in India killed >40,000 Polio, measles, herpes, hepatitis viruses Cancer, 15% or cancers worldwide are linked to viral diseases -eg Hep B, Hep C, Human Papilloma Virus (HPV)

Emerging and re-emerging diseases –HIV (emerging) –Cytomegalovirus (CMV, re-emerging) ~75% have CMV, but problems only arise when individual is immunosuppressed –Hantavirus –Ebolavirus New problems due to virus / environment changes. Humans change environment and life style very fast: –population density –living conditions (­ generally) –travel further & faster –agri- aqua-culture

New problems due to virus / environment changes (cont’d) Aqua Culture (fish farms) - close quarters = highly increased transmission of viruses - infect wild stock after release Polio (previously very prevalent) -almost all kids used to get polio while young (<2 years old) with no big effects -increased sanitation = less polio in youngsters **PROBLEM** may cause paralysis in 5+ year-olds Chicken Pox (type of Herpes virus) -Same problem as polio…may cause shingles in later life (much more severe)

BUT, not all virology research is immediately applicable to medicine –research tools (cloning vectors) - Retroviruses = Reverse Transcriptase Enzyme -cDNA library - useful for cloning genes (tells protein sequence without mass of introns) -RT-PCR (quantitative) - useful for measuring mRNA (unstable, difficult to measure directly) - thermostable DNA pol is helpful, but not essential Microarrays – RT required for probing - Viruses = useful cloning vectors - eg. Lambda Phage (precursor to Bacmids) - eg. M13 Phage (for sequencing) - ssDNA Phage, replicating form is dsDNA - Can insert dsDNA and end up with ssDNA - T4 DNA polymerase and ligase used in cloning –model systems (relatively simple) TMV (Tobacco Mosaic Virus) = RNA + only 1 protein…much easier to purify and study –asking questions about host functions (intimate association between life cycles)

What's needed? Anti-virus drugs equivalent to antibiotics. ?? Why so few??? Why are they not as effective as antibiotics??? –viruses replicate inside host cell (HIV in immune cells) HIV latency induced by drugs – remove drugs, HIV returns! –viruses essentially inert outside host –herpes virus latent between episodes of disease (hidden) – viruses don’t have many unique proteins to target (use host systems) –look for unique aspects of virus life cycle = antibiotic targets Can you target host functions? –eg. Host protease (furin targeted for SARS and HIV) –eg. Glycosylation (many virus particles require heavy glycosylation) – difficult because viruses use so many of host functions –many viruses have very different life cycles Possible Targets: - ds RNA induces interferon - reverse transcriptase/protease in retroviruses - thymidine kinase in herpes viruses (sufficiently different enough to target) –Better vaccines !! –?? make different vaccine for every virus –?? multivalent vaccines (type of response, Cell-mediated vs Antibody )