The Evolution of HIV

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The Evolution of HIV

• Biology and natural history of the virus

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Fig. 1.1 Global incidence of HIV/AIDS. Number
of cases and per cent of adults infected, ages
15-45. Data from UNAIDS (2005).
1/5th in South and SE Asia
3/5ths of HIV cases in Africa
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Three global epidemics
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Recent epidemic in Russia and Ukraine
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The epidemic in Africa
From UNAIDS (2006)
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In sub-Saharan Africa
Life expectancy at birth in Botswana
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Fig. 1.5 The life cycle of HIV
Extracellular stage transmission
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Intracellular stage replication
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• CD4 protein is found on T cells, HIV uses CD4
  to invade them
• CD4 serves important functions in the immune
  system

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• e.g. CD4 aids in binding of macrophages to helper
  T (TH) cells
• stabilizes antigen presentation to TH cell
• TH cells play a central role in both pathways of
  immunity

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HIV a retrovirusDNA is reverse-transcribed from
viral RNA by reverse transcriptase
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Intracellular replication stages
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How does HIV cause AIDS?
TEM of HIV budding (arrow) from a T lymphocyte
(image R. Hunt, Univ. S. Carolina)

• Simple answer depletion of T cells killed by HIV
  replicating within them suppresses immunity,
  leading to opportunistic infections
• Complete answer
• complex immune activation hastens collapse by
  providing host cells
• close phylogenetic relative, SIV, provides useful
  model for studying this

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Fig. 1.8a Viral load in an untreated patient

• rapid increase, followed by drop, steady recovery
  (reflects immune response)
• evolution within patient of declining target cell
  selectivity

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Fig. 1.8b T cell depletion

• decline, recovery, collapse of T cell population
• drastic decline in gut (vulnerable to pathogen
  attack)
• slow disease onset

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Fig. 1.8c Activation of the immune system

• remains highly activated throughout!
• enhances rate of destruction of HIV infected
  cells, but
• provides steady source of host T cells
• exhausts limited capacity to re-supply killed T
  cells

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The evolution of HIV

• Why do AZT and other antiviral drugs fail over
  the long term?

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Fig. 1.9 How AZT blocks DNA synthesis by HIV
reverse transcriptase
RT mistakes azido-thymidine (AZT) for the normal
nucleoside (T)
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Fig. 1.9 How AZT blocks DNA synthesis by the
reverse transcriptase of HIV
the azide group on AZT stops DNA synthesis and RT
falls off
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AZT treatments

• Initially, low doses dropped viral load,
  increased CD4 T cell counts
• Increasing doses, over time, lost effectiveness
• No evidence that patients enzymatic activation
  of AZT declined

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Evolution of AZT resistance

• A change in the genetic composition of patients
  viral population?
• To test
• Sample virus from patient over time as AZT
  treatment progresses
• Grow virus on cells in culture
• Test inhibitory action of increasing doses of AZT

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Fig. 1.11 Evolution of AZT resistance within
individual patients
from Larder et al. (1989)
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HIV populations can take only 6 months to evolve
high AZT resistance
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Some random reverse transcriptase mutations will
cause shape changes in the active site
(arrow), allowing them to recognize and not pick
up AZT
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Space-filling model of reverse transcriptase
from Cohen (1993). The large groove is where
RNA template and nucleotides bind.
Drug resistance mutations (in red includes the
AZTR mutations) are located within this groove
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Fig. 1.14 How populations of HIV evolve AZT
resistance (through natural selection within
patients)
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HIV mutation rates

• High replication rate 10 million to 100 million
  new virions per day (Ho et al. 1995, Wei et al.
  1995)
• High reverse transcriptase mutation rate (1
  mutation/genome/ replication)
• polymerase is error prone
• HIV lacks DNA repair