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Biology (Sci)
BIOL 303
Jonathan Witt

BIOL359 - Evolution Winter 2013 Chapter 1: A Case for Evolutionary Thinking: Understanding HIV 1.1.The Natural History of the HIV/AIDS Epidemic - HIV (Human Immunodeficiency Virus) causes AIDS (Acquired immune deficiency syndrome) - Epidemics: Influenza (1918), Black Death (1347-1452), Smallpox (1520) & AIDS (1981) - W.H.O – Global Death from Major Diseases o Heart attack (12.6%), Cancer (12.5%), Stroke (9.7%), Lower RTI (6.8%), AIDS (4.9%), Tuberculosis (2.7%) & Malaria (2.2%), etc. - HIV Infectious Rates Across the Globe o North America & western Europe much lower than sub-Saharan Africa - HIV infects when bodily fluid holding the virus (e.g. Blood or Semen) is transferred o Through sex, needle sharing, blood transfusion, childbirth & breastfeeding o Sub-Saharan Africa & India: Heterosexual sex o China: Drug injections, transfusion, & heterosexual sex o United Ststes & western Europe: Homosexual sex & needle sharing, then heterosexual sex - HIV prevention: 1 condom usage decreased the rate of transfer, but due to the effectiveness of long-term drug therapies, the percentage of risky sexual behavior increased, hence the rate of infection HIV increased again since 2000 - What is HIV? o Intracellular parasite that invades specific host cells & uses its enzymatic machinery (DNA Polymerase, Ribosomes & tRNA) & energy for replication, killing the host cell in the process o Extracellular/Infectious phase: Virion moves from host cell to another & transmission is possible o Intracellular/Parasitic phase: Virus replicates  Replicates by attaching gp120 protein to 2 host proteins (CD4 T cell receptor & Co-receptor)  Virion envelope fuses with host cell membrane, content enters the host cell  Diploid genome (2x SSRNA) & 3 proteins (Reverse transcriptase, integrase & protease)  Reverse transcriptase synthesizes HIV DNA from HIV’s RNA template  Integrase splices HIV DNA into host genome  HIV DNA is transcribed (host DNA Polymerase) & translated (host Ribosome) into HIV protein  Protease cleaves precursors into mature viral proteins  assembles  bud off  Drugs that interrupts virus’s life cycle almost certain also interfere with the host cells’ enzymatic functions  debilitating side effects - How Dose HIV Cause AIDS? o HIV parasitizes T helper cells & deprives the immune system’s supply of it. T helper cells play crucial role in response to invading pathogens, so the host is vulnerable to a variety of secondary infections o SIVsm: Simian Immunodeficiency virus related to HIV (infects monkeys)  Natural host: Sooty mangabey can tolerate infection with SIVsm  Rhesus macaques infected with SIVsm develops AIDS  The rhesus macaques with more aggressive immune system activation develops AIDS relatively fast o T cell life cycle  Stem cell (Bone Marrow)  Naïve T cell (Thymus – Long lived)  Activated @ lymph nodes & undergoes proliferation into effector T cells (Circulation – Short lived) & memory T cells (Lymphoid tissues – Long lived)  T cell lineages has a finite capacity for replication, this capacity is reduced with each cell division (Sustained immune activation during HIV infection ultimately deplete the body’s supply of T helper cells  Collapse of the host’s defenses) o 3 phases of untreated HIV infection  Acute phase: HIV virion enters host’s body and begins to replicate BIOL359 - Evolution Winter 2013  Majority of HIV strains binds to CCR5 Co-receptor (e.g. Dendritic cells, Macrophages, T cells – especially memory & effector T helper cells)  Significant increase in HIV virion concentration  Sharp decline in T cell population (killed by HIV via replication) o Hardest hit: Memory & Helper T cells in lymphoid tissues of the gut  Ends when virion concentration drops & host CD4 T cell counts recover somewhat o Virus runs short of host cells it can easily invade o Killer T cells begin to target infected host cells with HIV  Chronic phase: Immune system try to recover while continuing to fight the virus  Immune system remains highly activated, burns through the host’s supply of naïve & memory T helper cells o Replacement depends on naïve T cell production @ thymus o Thymic output declines with age & is impaired by HIV infection  Capacity to regenerate slowly erodes  Ends when the T cell concentration drops below 200 cells per cubic millimeter  AIDS: No longer functional immune system, opportunistic infections occurs  No treatment, HIV-infected individual with AIDS system can live 2 or 3 more years 1.2. Why Does AZT (Azidothymidine) Work in the Short Run, But Fail in the Long Run - AZT is similar in chemical structure to the nucleotide thymidine o Thymidine has –OH where the next nucleotide can be incorporated o AZT has – N 3 so reverse transcriptase cannot elongate the growing strand of DNA - Causes serious side-effects, can also fool DNA polymerase & interrupts DNA synthesis in host cells - However, after a few years, patients stopped responding to treatment o Patient’s own cellular physiology changed  AZT must be phosphorylated by the cells’ own thymidine kinase to be biologically active  Long term exposure renders less thymidine kinase production  less activated AZT  Experiment: Concentration of phosphorylated AZT didn’t change over time o Population of virions in the patient changed, where most become resistant to AZT over time  Resistant virion: Change the active site in reverse transcriptase enzyme, so its less likely to mistake AZT for the normal nucleotide  Viral strains present late in treatment with AZT was genetically different from v
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