Chapter 1.  A Case for Evolutionary Thinking: Understanding AIDS

• HIV and the AIDS epidemic
  • AIDS = acquired immune deficiency syndrome, caused by HIV.
  • HIV = human immunodeficiency virus, intracellular parasite, a retrovirus infecting and killing cells of the immune system.  Transmitted in bodily fluids (semen, blood, breast milk, etc.)
  • Two centers of the epidemic and modes of infection: heterosexual sex in sub-Saharan Africa; sex between men and/or needle sharing in North America and Europe (but see Fig. 1.1 for more geographical details – the epidemic is spreading).
• Biology and life cycle of HIV (See the very clear diagram in Fig. 1.3)
  • The virus is simple: 9 genes contained in a double RNA "chromosome" plus a protein coat.
  • HIV particle (virion) invades and ultimately kills T cell (attaches to CD4 receptor on cell surface, then to co-receptor protein), introduces:
    • RNA
    • Reverse transcriptase (RT)
    • Integrase
    • Protease
  • Viral RNA is transcribed to viral DNA using viral RT and machinery of host cell (ATP, enzymes, etc.)
  • Viral DNA incorporated into host nuclear DNA (by integrase) and transcribed to RNA.
  • Part of the RNA becomes "chromosome" of new virus particles, part becomes mRNA, is translated to viral proteins (including RT). Viral protease used to process viral proteins.
  • Viral particles (virions) are assembled, released into blood where they can infect more T cells or be transmitted to new host.
• The immune system, HIV and AIDS.
  • Self/non-self mechanism: cells of the body  have recognition proteins on surface, unique to individual, ignored by cells of immune system.  But immune system cells will respond to non-self items (e.g. foreign cells, viruses, fragments of virus particles, etc.)
  • High degree of specificity: cells of immune system produced in huge variety, each recognizes a specific non-self item (antigen).
  • Great diversity of cells and antibodies are produced by immune system:
    • Macrophages, engulf, display fragments of non-self items on cell surface
    • T cells, produced by thymus gland
    • B cells, produced by bone marrow
    • Antibodies: proteins binding to antigens, marking them for destruction by t cells.
    • AIDS results if number and diversity of HIV virions overwhelms ability of immune system to respond.  Illness and death are a result of opportunistic bacterial and fungal infections.
• How does HIV defeat the immune system?
  • RT is error-prone, makes many mistakes when inserting nucleotides into growing DNA strand during transcription.  There is no proofreading mechanism as in normal DNA to RNA transcription.
  • Point mutations arising during (reverse) transcription result in mutant virions, so genetic diversity of  virions increases during infection.  This overwhelms ability of immune system to produce corresponding diversity of T and B cells.
• Anti-HIV drugs: the AZT story (evolution of  resistance to AZT by HIV populations)
  • AZT = azidothymidine, a thymidine analog.  RT incorporates it (instead of thymidine) into growing DNA strand, this halts transcription.
  • If the active site of an RT molecule ignores AZT, then reverse transcription proceeds normally.  High mutation rate of  HIV multiplied by millions of virions ensures that some virions will be produced with AZT-rejecting RT.
  • This is evolution by natural selection, and involves these steps:
    • Transcription errors by RT result in mutant RT genes being expressed in next HIV generation.
    • This results in variability in RT enzyme function among virions.
    • Viral lineages with RT that ignores AZT survive, others don't (as long as AZT is present).
    • In time, entire virion population becomes AZT-resistant.
  • This is an example of a "Darwinian scenario".  Other examples abound.
  • Some questions about natural selection:
    • Is natural selection automatic?
    • Does natural selection work for the “good of the species”?
    • What determines the fitness effect of a trait?
• Why does HIV kill its host?
  • Should a parasite kill its host?
  • Virulence = tendency of pathogen to cause disease in host, is a function of pathogen  population growth rate.  So why is HIV so virulent? Why doesn't natural selection reduce virulence, producing longer survival of HIV populations?  Four hypotheses:
    • There are constraints on the biology of  the system which prevent reduction in virulence (e.g., there is no way of reducing RT error rate).
    • There are no mutations affecting virulence, hence no variation in virulence, so natural selection cannot reduce virulence.
    • Transmission rate hypothesis: natural selection favors high rates of virulence when partner exchange is frequent, low rates of virulence when partner exchange is infrequent.
    • Virulence results from trade-off between natural selection working at two levels: within hosts and between hosts.
• Natural resistance to HIV exists.
  • Mechanism: modification of structure of protein on T-cell surface ("coreceptor molecules") caused by mutation in gene encoding protein.  Mutation has produced the Delta32 allele
  • Frequency of Delta32 allele varies geographically: high in people of European ancestry, low in persons of Asian or African descent.  See Fig. 1.11.  Explanation?
    • Genetic drift?
    • Selection caused by plague in Europe in 14th. century (allele may also protect against plague bacterium)?
  • Will natural selection in human populations result in an increase in frequency of resistant individuals?
• Where did HIV come from?
  • Techniques and concepts used to answer this question: phylogeny, cladogram (phylogenetic tree), nodes, lineages.
  • Constructing cladograms: complicated, but based on assumption that genetically similar organisms have more recent common ancestor than do genetically dissimilar organisms.  See Fig. 1.12.
  • Conclusions: HIV-1 and HIV-2 have evolved from SIV's, jumped from monkeys and apes to human populations in Africa, multiple times.
  • Rapid evolution of new HIV strains makes development of anti-HIV drugs difficult.
• Implications of evolutionary biology for the AIDS epidemic:
  • Search for AIDS vaccine futile?
  • Continued evolution of resistance of HIV to antiviral drugs.
  • Will the frequency of resistance alleles increase in the human population?