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Chapter 1- Understanding HIV.docx

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BIOL 359
Jonathan Witt

BIOL 359 Janice Wong Evolution Chapter 1: A Case for Evolutionary Thinking: Understanding HIV HIV: is the virus that causes acquired immune deficiency syndrome (AIDS) Evolutionary biology devoted to understanding two things: 1. How populations change through time following modifications in their environment 2. How new species come into being. Evolutionary biologists study adaptation and diversity. 1.1| The Natural History of the HIV/AIDS Epidemic What is HIV? • An intracellular parasite that afflicts cells in the human immune system • Two phases in life cycle o Extracellular form of a virus is called a virion or virus particle  The virus moves from one host cell to another o Intracellular is the parasitic phase  The virus replicates • Is a retrovirus o Flow of genetic information is different o Flows from RNA to DNA, then mRNA to proteins • Uses the host cell’s own enzymatic machinery- polymerases, ribosomes, and tRNAs- in almost every step of the HIV’s life cycle • This makes it hard to treat • Drugs that interrupt the virus’s life cycle are almost certain to also interfere with the host cell’s enzymatic functions and therefore cause debilitating side effects How Does HIV cause AIDS? • HIV parasitizes the immune system cells, particularly helper T cells • Immune system’s supply of T cells is badly depleted • T cells play a crucial role in the response to invading pathogens • Host is no vulnerable to secondary infections • The host’s own immune response contributes to the development of immunodeficiency • T Cell life cycle o T cells derive from stem cells in the bone marrow o Activated T cells proliferate yielding effector and memory T cells o Naive and memory T cells are long lived o Effector T cells are short lived as they are actively engaged in the fight o T cell lineage has a finite capacity for replication • Throughout the chronic phase, the immune system remains highly activated o Due to the ongoing effort to control the HIV infection o Stimulation by proteins encoded by the virus o Destruction of regulatory T cells by the virus o The need to fight other pathogens slipping past the weakened gut defences • The immune system’s capacity to regenerate steadily erodes • The viral load climbs again and the CD4 T cell counts fall BIOL 359 Janice Wong Evolution • With so few helper T cells left, the immune system can no longer function • The patient develops AIDS • AIDS begins when HIV infection has progressed to a point where the immune system does not function properly • The syndrome is characterized by opportunist infections with bacterial and fungal pathogens that 1.2| Why does AZT Work in the Short Run, but Fail in the Long Run? • Azidothymidine, AZT • AZT blocks reverse transcriptase • HIV’s reverse transcriptase enzyme uses nucleotides from the host cell to build a DNA strand complementary to the virus’s RNA strand • AZT mimics a normal nucleotide and tricks the reverse transcriptase into picking it up and incorporating it into the growing DNA strand • But lacks the attachment site for the next nucleotide in the chain and the reverse transcriptase is now stuck • AZT interrupts the pathway to new viral proteins and new virions • AZT worked in early tests • However caused serious side effects o Sometimes fools DNAP and interrupts DNA synthesis in host cells • After a few years of use, patients stopped responding to treatment, and their CD4 cell counts began to decline • What happened? The population of virions living inside the patient changed so that the virions themselves would become resistant to disruption by AZT • Virions taken after 20 months on AZT were highly resistant, and were completely unaffected by AZT concentrations • Shows that populations evolve • Viral strains present late in treatment were genetically different from viral strains what had been present before treatment in the same host individuals • Mutations associated with AZT resistance were located in the active site of reverse transcriptase making the enzyme less likely to ass AZT instead of thymidine • HIV have the highest mutation rate of any virus • As the resistant virions reproduce and the non-resistant virions fail to propagate, the fraction of the virions that are resistant to AZT increases over time • Some additional mutations may further enhance the ability of reverse transcriptase to function in the presence of AZT • Shows: EVOLUTION BY NATURAL SELECTION o Changes in the genetic makeup of HIV populations over time have led to increased drug resistance • When the AZT therapy has been stopped, the proportion of the AZT-resistant virions in the viral populations has fallen back toward what it was before AZT treatment began BIOL 359 Janice Wong Evolution In summary 1. Transcription errors produce mutations in the reverse transcriptase gene. 2. The mutant virions pass their reverse transcriptase genes, and thus their AZT resistance or susceptibility to their offspring. AZT resistance is heritable 3. During treatment with AZT, some virions are better able to survive and reproduce than others. 4. The virions that persist in the presence of AZT are the ones with mutations in their reverse transcriptase that confer resistance  Heritable traits that lead to survival and reproductive abundance spread in populations  Heritable traits that lead to reproductive deficit disappear  Thi
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