A CASE FOR EVOLUTIONARY THINKING: UNDERSTANDING HIV.

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Kimball's Biology Pages has an excellent overview of the material.

 

INTRODUCTION

• HIV is an epidemic that regularly makes news.  HIV demonstrates how evolutionary biologists study adaptation and diversity (evolution of new species).

• This chapter addresses four evolutionary questions.
  1. Why is HIV/AIDS so hard to treat? Promising treatments such as AZT are worked out only to prove ineffective in the long run.
  2. Why are some people resistant to infection or progression?
  3. Why is HIV fatal?
  4. Is a vaccine possible?

1.1    The Natural History of Epidemic, HIV, the Immune System, and AIDS

Introduction: Who has it and Mode of Transmission

1. Distribution of HIV infections (Fig. 1.1)
   1. >40 million worldwide
   2. >23 million in sub-Saharan Africa, etc
2. Most HIV infections result of one of two different (but related) epidemics dating from 1980's and 1990's
   1. in Africa and Southeast Asia 
      1. transmitted primarily through heterosexual intercourse
      2. affects men and women equally.
   2. in the US and Europe
      1. mainly among homosexual men and intravenous drug users 
3. HIV infection rates by geographic areas
   1. rate of infection declining in industrialized countries
   2. WHY?

What is HIV? Some Background on Viruses and Retroviruses

• Viral diversity 
  • viruses are highly specific in the organisms they infect and the cell types they parasitize
• HIV structure [Fig. 1.3]
  1. retrovirus with two RNA strands
  2. reverse transcriptase
  3. gp 120 (surface protein)
• HIV attacks helper T cells that have the protein CD4 on their surface.

• HIV life cycle [Fig. 1.3]
  1. HIV virion stage
     1. extracellular, active particle
  2. HIV gp120 surface protein binds to the CD4 receptor and co-receptor proteins on the cell membrane of human macrophages and helper T cells of the immune system
  3. Steps 3-8

HOW DOES HIV CAUSE AIDS

• CD4+ T cells are killed by killer T cells or by the virus
• HIV kills people indirectly by weakening the immune system, allowing opportune infections.

1.2    Why Does AZT Work in the Short Run, but Fail in the Long Run?

• the azidothymidine in AZT substitutes for thymidine and terminates viral DNA production
• Viral mutations in the reverse transcriptase gene alter the shape of the active site
• These virions will be naturally selected for.
• in the absence of AZT, selection favors back mutations to the original active site configuration. Why?
• mutations of env genes enable virions in lungs to better evade macrophages of lungs (versus macrophages in the blood) cause divergence in the same individual.

    How Does HIV Defeat the Immune Response?

• HIV has an extraordinary high mutation rate
  1. reverse transcription lacks the error correcting enzymes
  2. >50% of the viral DNA transcripts have at least one mistake; thousands of viral generations occur/individual.
• high mutation rate may be an adaptation to produce new epitopes and escape detection by the immune system

1.3 Why is HIV Fatal?

• proximate cause (how)
  1. With the removal of helper-T cells, there is essentially no immune response.
  2. Without an immune response, no parasite, cancer, etc., no matter how mild, can  be stopped by the body.
• ultimate cause (why--evolutionary response)
  1. Why hasn't HIV evolved to be less virulent?
  2. Are there constraints?
  3. The transmission rate hypothesis
     1. natural selection has adjusted the rate of virulence in HIV.
     2. costs and benefits of rapid growth for virion
     3. Which evolutionary strategy succeeds depends on the degree of sexual promiscuity.
  4. HIV-2 is much more benign than HIV-1, despite a similar life cycle. Center of incidence in West Africa

1.4    Why are Some People Resistant to Infection by HIV?

1. Two patterns of resistance have been confirmed
   1. some people repeatedly exposed to the virus are not infected
   2. some people who are infected live much longer than expected
2. there is a molecular basis for resistance
   1. non-random distribution suggests that selection in the past has favored the allele in some populations but not others

1.5     Could a Vaccine Provide Protection from the Diverse Strains of HIV?

Cellular Defenses: The Immune Response to Infection

• Steps in immune response 
  • macrophages destroy virions in blood stream and infected cells
  • each helper T cell responds to a <10 epitopes from invading pathogens displayed by macrophages
    1. epitope: foreign proteins displayed by macrophages
  • Helper T cells stimulate cell-mediated and humoral immune responses.
• vaccines = epitopes from killed or incomplete virions
• high mutation rate of HIV may be an adaptation to produce new epitopes

Where Did HIV Come From?

• A phylogeny of some retroviruses [Fig. 1.12]
  1. HIV phylogeny shows virus has moved between host species.
  2. parsimony analysis indicates HIV's are derived from monkey SIV viruses

What, if Anything, Does Evolutionary Biology have to Say About Ways to Stem the AIDS Epidemic?

• Continue to study ways to stop the functioning of the transcriptase gene.
• Vaccines are probably not going to work long term.
• Behavior changes can have great success.

HIV updates

1.  Anticipation grows for HIV vaccine
2. AIDS conference closes on gloomy note
3. HIV targets active genes in cells
4. Promising multi-strain HIV vaccine candidate emerges
5. New AIDS drug discoveries to battle drug-resistant HIV strains
6. Genetic mutation influences spread of AIDS; African population lacks mutation
7. New method of turning off viruses may help control HIV infection, says Jefferson scientist
8. Did modern medicine cause AIDS. from the San Francisco Chronicle

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