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Chapter 1

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BIOL 359
Jonathan Witt

Chapter 1:ACase for Evolutionary Thinking: Understanding HIV • Evolution of HIV (human immunodeficiency virus) • Infection w/ HIV causesAIDS (acquired immune deficiency syndrome) • HIV is emerging pathogen, and rapidly evolves drug resistance • Evolutionary biology devoted to understanding how populations change over time and how new forms of life arise. 1.1 The Natural History of HIV Epidemic • HIV epidemic most devastating in sub-SaharanAfrica (1/20 adults have HIV) • HIV/AIDS- first seen has pneumonia and cancer among men who have sex with men • Mainly men are effected when compared to women and children • People infected peaked in some countries but continues to climb in others How does HIV spread, and How can it be slowed? • Infections starts when bodily fluid carries the virus from an infected person directly onto a mucous membrane or into the bloodstream of an uninfected person • In sub-saharanAfrica + parts of southeast Asia; heterosexual sex most common mode of transmission, but in Europe and northAmerica male-male sex and needle sharing predominant • Data on men who have sex with men shows having receptive anal intercourse with casual partners without protections is dangerous • Use of antiviral drugs lower risk of infected mother passing virus to infants by 40%, and transmission among men who have sex with men • The number of infections fell from mid 1980s to early 1990s but now annual number of infections been rising steadily • Survey suggests introduction of effective long-term drug therapies, which for some individuals has at least temporarily transformed HIV into a manageable chronic illness, has also prompted an increase in risky sexual behavior What is HIV? • Intracellular parasite incapable of reproducing on its own. • Invades specific types of cells in human immune system • Kills host cell • Life cycle has 2 phases: o Extracellular phase: virus moves from one host cell to another, and can be transmitted from host to host o Intracellular: replication phase where virus replicates • HIV adheres to CD4 and coreceptor fusion of virions envelops with hosts cell membranespill contents of viron into cell (virus’s genome and viral enzymes) infiltration of host cells DNAwith HIV genome host cell RNApolymerase transcribes viral genome to viral mRNA host cells ribosomes synthesize viral proteins new virions assemble at host cells membrane and bud off • Challenging to find drugs that interrupt viral life cycle without also disrupting the host cells enzymatic functions How does the immune system react to HIV? • dendritic cells capture virus and present bits of its proteins to naïve helper T cells, once activated these naïve cells divide to produce effector helper T cells which help coordinate immune response via cytokines • 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 • Effector helper t cells help activate killer T cells, which destroy host cells infected with virus.. also recruit macrophages • Effect T cells short lives, but few become long lived memory helper T cells. How does HIV cause AIDS? • Different strains of HIV exploit different coreceptors • Most strains use CCR5 so cells with CD4 and CCR5 vulnerable to HIV (macrophages, effector helped T cells, memory helper T cells) • Progress of HIV infection monitored by measuring conc. of HIV virions in blood stream and concentration of CD4 T cells in bloodstream • Untreated infection has 3 phases: o Acute: HIV virions enter hosts body and replicate explosively. Ends when viral replication slows and concentration of virions in bloodstream drops and CD4 T- cell counts recover somewhat o Chronic: few symptoms present, HIV continues to replicate, concentration of virions in blood stabilize for a while but eventually rise again, conc. of CD4 Tcells fall o AIDS: begins when concentration of CD4 T cells in blood drops below 200 cells/cubic cm, immune system has begun to collapse so easily infected by any virus and bacteria  HIVs attack on CD4 T cells destroys large fraction of T cells (which decreases the number of CD4 cells)  HIV also damages other tissues decreasing barrier between gut bacteria and bloodstream. Then bacteria in blood triggers high level of immune activation to which HIV infection itself also contributes  HIV replicated most efficiently in activated CD4 T cells, so immune systems best efforts to douse the HIV infection just add fuel to the fire.  Eventually patients T cell concentrations inexorably fall, immune system loses ability to fight pathogens resultingAIDS  To prevent HIV leading toAIDS is prevent it from replicating 1.2 Why does HIV Therapy Using Just One Drug Ultimately Fail? • To fight HIV drugs target should include viruses protease, integrase and reverse transcriptase • AZT interferes with reverse transcriptase (so similar to thymine so it fools reverse transcriptase into picking it up and incorporating it into growing DNA.. but thymine has –OH group andAZT has –N3 …hydroxyl group is where reverse transcriptase attaches next nucleotide so withAZT its stuck o AZT caused side effects because fooled patients own DNApoly as well  After few years patients stopped responding. Why? Does AZT alter patient’s physiology? AZT could lose effectiveness in either or both of two ways: • i. Patients own cellular physiology could change o After entering cellAZT has to be phosphorylated via cells thymidine kinase maybe after long term exposure causes cells to make less thymidine kinase but this hypothesizes was rejected after testing!  Conc. of phosphorylatedAZT did not change over time ii. Does AZT alter the population of virions living in the patient? • Virions living inside patient could change so virions themselves become resistant to disruption byAZT- this is what was seen to be happening • Drugs resistant populations of HIV evolve within just six months What makes HIV resistant toAZT? • Found that viral strains present late in treatment were genetically different from viral strains that had been present before treatment in the same hosts • Mutations associated withAZT resistance often same from patient to patient and caused amino acid change in reverse transcriptase’s active site • Altered reverse transcriptase able to remove AZT and continue building DNAcopy, enables HIV virions to replicate in presence of AZT • Reverse transcriptase prone to mistakes, so at least one DNAtranscript has a mutation, and w/ thousands of generations of HIV replication enormous number of reverse transcriptase variants in every host so one or more variants contain amino acid substitution that improves reverse transcriptase ability to recognize and remove AZT • Eventually withAZT intake replication of unaltered HIV variant suppressed but resistant mutants exist… eventually fraction of virions resistant toAZT increases over time • Process of change over time in composition of viral population is evolution by natural selection • NowAZT alone is not effective for AIDS therapy Evolution by Natural Selection 1. Replication errorsmutations in reverse transcriptase gene different virions produce different reverse transcriptase with varying resistance toAZT 2. Mutant virions pass reverse transcriptase gene to offspring (heritable) 3. Some virions better able to survive when treated withAZT 4. virions that persist in presence ofAZT have mutation in reverse transcriptase that confer resistance • Composition of viral population within host changes over time • Evolution by natural selection is automatic consequence of heritable differences in replication • Natural selection can happen in any population where there is heritable variation in reproductive success! Understanding Evolution Helps Researchers Design Better Therapies • Drugs in use for HIV: o Coreceptor inhibitor: prevent HIV from entering host cells in first place… interfere with CCR5 o Fusion inhibitors: interfere with HIVs gp120 or gp41 o Reverse transcriptase inhibitors: likeAZT, mimic normal building blocks of DNAor interfere with enzymes active site o Integrase inhibitors: block HIVs DNAinto host genome o Protease inhibitors: prevent HIVs protease enzyme from cleaving viral precursor proteins to produce mature components for new virions • With high mutation rate, short generation time, large population size, HIV generates many mutant genomes that variants with crucial combination of mutations likely to
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