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 THE HIV/AIDS Epidemic

Introduction: Who has it and Mode of Transmission

1. Distribution of HIV infections (Fig. 1.1)
   1. >40 million worldwide
   2. >25 million in sub-Saharan Africa
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. The number of cases continues to increase in Asia and Africa. (Fig. 1.1 b)
      1. Life expectancy in Botswana has fallen >50% 1980-2005 (Figure 1.2)
   2. rate of infection slowly increasing in industrialized countries
   3. Figure 1.3 Successful HIV/AIDS prevention
      1. As condom use went up, the incidence of HIV infection went down
   4. Figure 1.4 Rates of new HIV diagnosis and other sexually transmitted diseases among men who have sex with men in London
      1. STDs including HIV are on the rise because of unprotected sex

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. 1.5]
  1. retrovirus with two RNA strands
  2. gp 120 (surface protein)
• HIV attacks helper T cells that have the protein CD4 on their surface.

• HIV life cycle [Fig. 1.5]
  1. HIV virion stage (extracellular, active particle) encounters a host cell
  2. The HIV virion invades a host cell by binding to two proteins on the cell's surface
     1. 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. Virion spills its contents (RNA and 3 proteins: reverse transcriptase, integrase, and protease) into host cell
  4. Reverse transcriptase synthesizes HIV DNA
  5. Integrase splices HIV DNA into host's DNA
  6. The host cell's RNA polymerase transcribes the viral genome into messenger RNA
  7. the host cell's ribosomes transcribe the viral mRNA into precursor proteins
  8. HIV's protease cleaves the precursors, yielding mature viral proteins
  9. New virions assemble in the host cell's cytoplasm
  10. New virions bud from the host cell's membrane.

HOW DOES HIV CAUSE AIDS

1. The simple answer
   1. Infected CD4+ T cells of the immune system are killed by killer T cells or macrophages or by the virus when it escapes the cell
   2. HIV kills people indirectly by weakening the immune system, which collapses (AIDS) allowing opportune infections which result in death.
2. A more complex answer
   1. Figure 1.8 The general pattern of progression of an untreated HIV infection
      1. an acute phase, in which the host may show general symptoms of a viral infection;
         1. The viral load spikes then falls as the host mobilizes an immune response which then fails.
      2. a chronic phase in which the host is largely asymptomatic, but
         1. the viral load climbs
         2.  viral population often evolves the capacity to infect a greater variety of host cells
      3. an AIDS phase

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

1. the azidothymidine in AZT (Figure 1.9) substitutes for thymidine and terminates viral DNA production
   • it lacks the attachment site for the next nucleotide in the chain.
2. HIV populations evolve resistance to AZT within individual patients (Figure 1.11)
   • As therapy continued, higher concentrations of AZT were required to curtail the replication of viruses
3. Viral mutations in the reverse transcriptase gene alter the shape of the active site enabling it to recognize AZT (Figure 1.13)
4. These virions will be naturally selected for (Figure 1.14).
5. Can understanding how resistance evolves help researchers design better treatments? (Box 1.1)
   • Figure 1.15 Successes of highly active antiretroviral therapy (HAART)
   • Fusion inhibitors Reverse transcriptase inhibitors Integrase inhibitors Protease inhibitors
6. in the absence of AZT, selection favors back mutations to the original active site configuration. Why?
   1. AZT alters the selective pressures imposed on HIV

    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?

1. 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.
2. ultimate cause (why--evolutionary response)
   1. Killing the host is an example of short-sighted evolution

Short-Sighted Evolution

1. HIV populations evolve inside individual hosts in response to selection imposed by the immune system.
   1. The host's immune system recognizes epitopes on HIV and HIV infected cells
   2. Evolution of the HIV population within an individual patient (Figure 1.17).  Virions diverge genetically over the course of the infection to evade the host's immune system, until they weaken and kill the host
2. Why hasn't HIV evolved to be less virulent?
   1. Are there constraints?
   2. 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.
   3. 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. 32 base pair deletion in co-receptor CCR5
   2. Figure 1.20:  The frequency of the CCR5-delta 32 allele in the Old World. The delta 32 allele is at highest frequency in northern Europe. From there its frequency declines to the south and to the east.
   3. non-random distribution suggests that selection in the past has favored the allele in some populations but not others

1.5  Where Did HIV Come From?

• The family tree (phylogeny) of HIV and related retroviruses [Fig. 1.21]
  1. This tree shows the evolutionary relationships among the two major forms of HIV, called HIV-1 and HIV-2, and the immunodeficiency viruses that afflict nonhuman primates
  2. HIV phylogeny shows virus has moved between host species.
  3. parsimony analysis indicates human HIV's are derived from monkey and chimp SIV viruses

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

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

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. Weblinks from textbook website

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