Evolution Lecture 2: HIV Evolution Continued

1
Evolution Lecture 2 HIV Evolution Continued
2
HIV Evolution and Natural Selection

• Transcription errors produce mutations in the
  reverse transcriptase gene. Virions carrying
  mutant reverse transcriptase gene produce
  versions of the reverse transcriptase enzyme that
  vary in their resistance to AZT
• The mutant virions pass their reverse
  transcriptase genes, and thus their AZT
  resistance or susceptibility, to their offspring.
  In other words, AZT resistance is heritable.
• During treatment with AZT, some virions are
  better able to survive and reproduce than others
• The virions that persist in the presence of AZT
  are the ones with mutations in their reverse
  transcriptase genes that confer resistance.

3
(No Transcript)
4
Back Mutations

• AZT resistant populations do not reproduce
  efficiently when AZT treatment is halted
• Back-mutations restore AZT resistant rev. trans.
  To the normal rev. trans. When AZT is not
  present. The original configuration is then
  favored by natural selection.

5
Understanding Resistance Evolution and Further
Treartments

• Since HIV evolves so quickly, what we need is to
  increase the number of mutations a virion needs
  to survive. We would like to do this so that the
  number of mutations required becomes prohibitive
  to survival
• Add new pressuresa cocktail of drugs
• Rev. trans. inhib
• Protease inhib.
• Fusion inhib
• Integrase inhib

6
Selection Pressure from Killer T-4 Cells

• Killer T-4 cells Recognize epitopes (viral
  proteins displayed on the surface of the infected
  cell).
• HIV evades detection by changing epitopes
• HIV produces 10-100 million virions a day, with
  an abundance of mutation and changed epitopes.
• Over 10 years, virions gp 120 gene diverged by
  8(2 difference in human and chimpnot a fair
  comparison).

7
Why does divergence asymptote?
Immune System Collapse, therefore no selection
to make novel epitopes
8
Host Switching

• CCR5 and CXCR4 are two types of co-receptors
  found on T4 cells. CCR5 replicates quickly and
  thus are infected first.
• As infection increases, HIV will switch to CXCR4
  (b/c they begin to divide more rapidly to take
  over for the decreasing CCR5).
• This ultimately hastens the death of the host.
  Why would this happen?

9
Natural Selection and Evolution are Not Goal
Oriented.

• HIV population in a single host evolves itself
  out of existence by killing that hostunless it
  spreads.
• Those that attack both CCR5 and CXCR4 are
  probably good at replication and infection.
• This helps them overcome another level of
  selectionstrains that reproduce more are found
  in higher quantities in bodily fluids and are
  thus able to become transmitted to other hosts
  more efficiently!!!
• Therefore their lineage does not die

10
Benign Forms of Aids and Low Transmission

• Sydney Bloodbank case and the special strain of
  aids that only infects CXCR4. Not as deadly b/c
  it does not reproduce efficiently
• Lack of portion of Nef protein does not allow the
  virus to gain entry into cell, boost viral
  replication, and thus less immune response from
  host.
• HIV-2 poor transmission among hosts and not as
  deadly
• Why are these strains so rare in nature?
  Inability to reproduce efficiently limits the
  concentration of virions in hosts blood, thus
  poor transmission.

11
Review of the two levels of selection in nature
against aids

• Variation in levels of ability for virus to
  survive and reproduce in host
• Variation in ability to become transmitted from
  host to host.
• These two types of selection are obviously tied.
  Think of an example where being good at the first
  limits being good at the second?

12
Selection Against Host and Response

• Some humans have unusual coreceptors on the
  surfaces of their cells.
• Deletion of 32 bp in CCR gene, bars virion from
  entrance.
• In parts of Europe gt14 of population has this
  gene. Why?
• Natural selection?
• Drift?small populationsVikings?????

13
(No Transcript)
14
HIV Origin and Reconstruction of Evolutionary
History

• Phylogenydiagrams evolutionary relationshipsa
  hypothesis.
• How to read a tree
• Node..branching point for common ancestors
• Branches (internodes)line of evolution leading
  to descendants
• Branch length may indicate genetic distance or
  time (in some instances)
• Monophyly, paraphyly, and polyphyly

15

• HIV-1 and HIV-2 Not related
• HIV-2 in humans related to Sooty
• Mangabey
• SIVcpz was transmitted to humans by chimps

16
Transmitted from chimps 3 times
17
When Did HIV Move from Chimps to Humans
18
(No Transcript)
19
(No Transcript)
20
Legal Cases Involving Aids Evolution

• 1998-Lafayette, LA, Woman claimed physician
  injected her with HIV infected patient.
• In Florida a woman claimed to have obtained HIV
  from dentist.