HIV-1 evolution in response to immune selection pressures

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HIV-1 evolution in response to immune selection
pressures BISC 441 guest lecture Zabrina
Brumme, Ph.D. Assistant Professor, Faculty of
Health Sciences Simon Fraser University
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http//www3.niaid.nih.gov/topics/HIVAIDS/Understan
ding/Biology/structure.htm
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HIV evolution in a single individual 12 year
period
eg Shankarappa et al, J Virol 1999
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On a global level
BD Walker, BT Korber, Nat Immunol 2001
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HIV subtypes are differentially distributed
throughout the world
http//www.hiv.lanl.gov
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Why does HIV evolution and diversification occur
so rapidly?
1. High mutation rate HIV reverse transcriptase
makes 1 error per replication cycle Recombination
Host factors APOBEC 3G 2. High replication rate
up to 1010 virions/day in untreated
infection 3. Lifelong infection 4. High numbers
of infected individuals worldwide 5. Multitude of
selection pressures - antiretroviral drugs -
immune selection pressures
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• My research program combines molecular biology
  and computational approaches to
• Study HIV-1 evolution in response to selection
  pressures imposed by cellular immune responses
  (immune escape)
• Use this information to identify characteristics
  of effective anti-HIV immune responses and other
  information that may be useful to vaccine design

humoral (antibody) responses are important too!
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HLA class I alleles present HIV-derived peptide
epitopes on the infected cell surface, thus
alerting CTL to the presence of infection
HLA
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HLA class I alleles act as a selective force
shaping HIV evolution through the selection of
immune escape mutations
HLA
CTL Escape Mutant
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HLA genetic diversity protects us against diverse
infectious diseases
Individual
B
A
C
Population HLA-A 1757 alleles HLA-B 2338
alleles HLA-C 1304 alleles
as of January 2012. http//hla.alleles.org/nomen
clature/stats.html
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Immune escape pathways are broadly predictable
based on host HLA
Moore et al Science 2002 Bhattacharya et al
Science 2007, Brumme et al PLoS Pathogens 2007
Rousseau et al J Virol 2008 Kawashima et al
Nature 2009
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Mapping sites of immune escape across the HIV-1
genome first, a brief primer on techniques and
challenges
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Identifying patterns of host-mediated evolution
in HIV
Brumme laboratory
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Assemble large cohort of HIV-infected individuals
Identifying patterns of host-mediated evolution
in HIV
Brumme laboratory
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Assemble large cohort of HIV-infected individuals
Identifying patterns of host-mediated evolution
in HIV
Undertake host (HLA class I) and HIV genotyping
Brumme laboratory
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Assemble large cohort of HIV-infected individuals
Identifying patterns of host-mediated evolution
in HIV
Undertake host (HLA class I) and HIV genotyping
Apply statistical methods to identify patterns of
HIV adaptation
Brumme laboratory
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Assemble large cohort of HIV-infected individuals
Identifying patterns of host-mediated evolution
in HIV
Undertake host (HLA class I) and HIV genotyping

Apply statistical methods to identify patterns of
HIV adaptation


Note these steps are harder and more complicated
than they appear
Brumme laboratory
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Pt1 ..TSNLQEQIGW.. B57 Pt2 ..TSTLQEQIGW..
B57- Pt3 ..TSNLQEQIGW.. B57 Pt4
..TSTLQEQIGW.. B57- Pt5 ..TSTLQEQIGW..
B57- Pt6 ..TSNLQEQIAW.. B57 Pt7
..TSTLQEQITW.. B57- Pt8 ..TSNLQEQIGW.. B57
TW10 epitope
B57
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Susceptible
Adapted
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Are escape mutations in HIV-1 accumulating at the
population level?
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Example escape in B51-TI8 epitope
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Increased prevalence of I135X in populations with
high B51 prevalence
Kawashima et al, Nature 2009
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Is it possible that HIV-1 is acting as a
selective pressure on humans??
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Vertical transmission of HIV (and genetic
inheritance of HLA)
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• HIV Immune escape pathways are broadly
  predictable based on host HLA

• Characterization of sites, pathways, kinetics of
  immune escape mutations will help identify
  regions for inclusion in vaccine design

• Information on common escape pathways can be
  incorporated into immunogen design to block
  preferred mutational escape pathways

• Evidence for accumulation of escape mutations in
  contemporary HIV-1 sequences

• Potential for HIV-1 selection on humans??