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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
http://www3.niaid.nih.gov/topics/HIVAIDS/Understanding/Biology/structure.htm
On an individual level….
Time since infection
HIV evolution in a single individual: 12 year period
eg:: Shankarappa et al, J Virol 1999
On a global level…
BD Walker, BT Korber, Nat Immunol 2001
HIV subtypes are differentially distributed throughout the world
http://www.hiv.lanl.gov
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
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 antiHIV immune responses and other information that may be
useful to vaccine design
*humoral (antibody) responses are important too!
HLA class I alleles present HIV-derived peptide epitopes on the
infected cell surface, thus alerting CTL to the presence of infection
HLA class I alleles act as a selective force shaping HIV
evolution through the selection of immune escape mutations
“CTL Escape Mutant”
HLA genetic diversity protects us against diverse
infectious diseases
Individual:
A
B
C
Population:
HLA-A = 1757 alleles*
HLA-B = 2338 alleles*
HLA-C = 1304 alleles*
*as of January 2012. http://hla.alleles.org/nomenclature/stats.html
HIV adapts to the HLA class I alleles of each host it
passes through
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
Mapping sites of immune escape across the HIV-1 genome:
…first, a brief primer on techniques and challenges…
Identifying patterns of
host-mediated
evolution in HIV
Brumme laboratory
Identifying patterns of
host-mediated
evolution in HIV
Brumme laboratory
Assemble large cohort of
HIV-infected individuals
Identifying patterns of
host-mediated
evolution in HIV
Assemble large cohort of
HIV-infected individuals
Undertake host (HLA class I)
and HIV genotyping
Brumme laboratory
Identifying patterns of
host-mediated
evolution in HIV
Assemble large cohort of
HIV-infected individuals
Undertake host (HLA class I)
and HIV genotyping
Apply statistical methods to
identify patterns of HIV
adaptation
Brumme laboratory
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
*
*
*
Note: these steps are harder
and more complicated than
they appear
B*57
not B*57
Pt1:
Pt2:
Pt3:
Pt4:
Pt5:
Pt6:
Pt7:
Pt8:
..TSNLQEQIGW..
..TSTLQEQIGW..
..TSNLQEQIGW..
..TSTLQEQIGW..
..TSTLQEQIGW..
..TSNLQEQIAW..
..TSTLQEQITW..
..TSNLQEQIGW..
B*57+
B*57B*57+
B*57B*57B*57+
B*57B*57+
T
0
4
N
4
0
p = 0.03
TW10
epitope
B*57
HIV-1 Gag:
Immune escape map
Susceptible
Adapted
Are escape mutations in HIV-1 accumulating at
the population level?
Transmission and reversion of escape mutations
nonB*57
B*57
selection
nonB*57
reversion
Failure to revert leads to accumulation of escape
variant at the population level
nonB*51
B*51
nonB*51
Example: escape in B*51-TI8 epitope
B*51-associated I135X mutation
HIV Reverse Transcriptase
Increased prevalence of I135X in populations with high B*51
prevalence
75
% I135X in B*51-
Kumamoto
R=0.91
p=0.0006
50
London
Perth
25
Vancouver
Gaberone
Barbados
Durban
0
Oxford
Lusaka
10
20
% HLA-B*51 Prevalence
Kawashima et al, Nature 2009
Is it possible that HIV-1 is acting as a selective
pressure on humans??
Vertical transmission of HIV (and genetic inheritance of HLA)
Mothers with protective
HLA alleles less likely to
transmit HIV to child
nonB*57
B*57
50% chance
B*57
HIV-infected children who
inherit protective alleles have
improved chances of survival
nonB*57
B*57
If B*57
improved
survival
Summary and Conclusions
- Strong evidence of HLA-associated immune selection on HIV
- 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??