What is HIV? Life cycle of HIV 1. HIV encounters host cell (helper T cell) 2. HIVs gp120 surface protein binds to CD4 and then to coreceptor (CCR5 or CXCR4) on surface of host cell 3. HIV virion fuses with the host cell HIVs RNA genome and enzymes enter the host cells cytoplasm 4. HIVs reverse transcriptase enzyme synthesizes HIV DNA from HIVs RNA template 5. HIVs integrase enzyme splices HIVs DNA genome into host cells genome 6. HIVs DNA genome transcribed into HIV mRNA by host cells RNA polymerase 7. HIVs mRNA is translated into HIV precursor proteins by host cells ribosomes 8. New generation of virions assembles at the membrane of the host cell 9. New virions bud from the host cells membrane 10. HIVs protease enzyme cleaves precursors into mature viral proteins, allowing the new virions to mature How does the Immune System React to HIV? Dendritic cells capture the virus and present bits of its proteins to nave helper T cells Once activated, nave cells divide to produce effector helper T cells Effector helper T cells stimulate B cells displaying the same bits of viral protein to mature into plasma cells, which make antibodies that bind and in some cases inactivate the virus Also activate killer T cells that destroy host cells infected with the virus Effector T cells are short lived but some become long lived memory helper T cells How does HIV cause AIDS? Macrophages, effector helper T cells and memory helper T cells vulnerable to HIV because of CD4 and CCR5 Acute phase HIV virions enter the hosts body and replicate explosively, so concentration of CD4 T cells plummets Chronic phase- patient has few symptoms but HIV continues to replicate Concentration of virions in the blood stabilizes for a while but eventually rises again and concentrations of CD4 T cells falls A model for how HIV causes AIDS HIV infects CD4+ T cells in gut, induces immune activation, replicates most efficiently in activated CD4+ T cells (immune system activation causes effector T-cell proliferation) Proliferation of T cells gives HIV more target cells Steady supply of target cells allows HIV to replicate prolifically HIV directly and indirectly induces immune activation and replicates in activated immune system cells When the ongoing battle damages the immune system to the point that it can no longer produce enough T cells to function properly, AIDS begins Why does HIV therapy using just one drug ultimately fail? AZT is similar in structure to T that it fools reverse transcriptase to pick it up and incorporate it into growing DNA strand and cant add more nucleotides Populations of virions within individual patients change to become resistant to AZT and populations evolve Evolution by Natural Selection 1. Replication errors produce mutations in reverse transcriptase genes that vary in their resistance to AZT 2. Mutant virions pass their reverse transcriptase genes and AZT resistance to offspring, so resistance is heritable heritable traits that lead to survival and abundant reproduction spread in populations. Heritable traits that lead to reproductive failture disappear. This is evolution by natural selection Understanding evolution helps researchers design better therapies By reducing genetic variation for resistance in virion population, cocktail of drugs that target different points in HIVs life cycle limit evolution of resistant strainshas dramatically improved patient survival HAART = highly active antiretroviral therapy Evolution of HIV strains resistant to multiple drugs Sometimes HIV populations evolve resistance even in patients taking multidrug cocktails Risk is highest in patients who fill most but not all of their prescriptions After Human populations evolving as a result of HIV pandemic? For a population to evolve, it must harbor genetic differences among individuals A missing coreceptor In human populations, some individuals carry alleles that make them resistant to infection with HIV 32 allele mutant form that has a 32-base-pair deletion in DNA HIV is too new a human disease to have triggered substantial evolutionary change in human populations Humans carry a loss-of-function mutation in the retrocyclin gene that appears to increase our susceptiblity to HIV. An allele with the back-mutation might be protective, but no such allele is known. Where did HIV come from? HIV-1 and HIV-2 transmitted to humans from different sources HIV-2 originated in sooty mangabeys HIV-1 transmitted to humans from chimpanzees Monkey SIV causes little to no disease but causes disease in humans and chimps