1. 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

4. Virus replication is dependent on many host cell proteins, enzymes, pathways and molecules “(factors”), and is accomplished through multiple virus-host interactions. Some interactions assist replication whereas others impede. Being a “successful” virus, HIV has found a way to overcome the major barriers imposed by the cell. Shifting the balance back towards the cell may be an approach to therapeutic rescue.

6. On an individual level….
Time since infection

7. HIV evolution in a single individual: 12 year period
eg:: Shankarappa et al, J Virol 1999

8. On a global level…
BD Walker, BT Korber, Nat Immunol 2001

9. HIV subtypes are differentially distributed throughout the world

10. 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

11. 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!

12. HLA class I alleles present HIV-derived peptide epitopes on the infected cell surface, thus alerting CTL to the presence of infection
CTL
HLA

13. HLA class I alleles act as a selective force shaping HIV evolution through the selection of immune escape mutations
CTL
CTL
HLA
“CTL Escape Mutant”

14. 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

15. HIV adapts to the HLA class I alleles of each host it passes through

16. 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

17. Mapping sites of immune escape across the HIV-1 genome:
…first, a brief primer on techniques and challenges…

18. Identifying patterns of host-mediated evolution in HIV
Brumme laboratory

19. Identifying patterns of host-mediated evolution in HIV
Assemble large cohort of HIV-infected individuals
Identifying patterns of host-mediated evolution in HIV
Brumme laboratory

20. Identifying patterns of host-mediated evolution in HIV
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

21. Identifying patterns of host-mediated evolution in HIV
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

22. * * * * Identifying patterns of host-mediated evolution in HIV
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

23. B*57 4 not B*57 B*57 N T p = 0.03 Pt1: ..TSNLQEQIGW.. B*57+4
not B*57
B*57 N T
p = 0.03
Pt1: ..TSNLQEQIGW.. B*57+
Pt2: ..TSTLQEQIGW.. B*57-
Pt3: ..TSNLQEQIGW.. B*57+
Pt4: ..TSTLQEQIGW.. B*57-
Pt5: ..TSTLQEQIGW.. B*57-
Pt6: ..TSNLQEQIAW.. B*57+
Pt7: ..TSTLQEQITW.. B*57-
Pt8: ..TSNLQEQIGW.. B*57+
TW10 epitope
B*57

24. HIV-1 Gag:
Immune escape map
Susceptible
Adapted

25. Are escape mutations in HIV-1 accumulating at the population level?

26. Transmission and reversion of escape mutations
non-B*57
non-B*57
reversion
B*57
selection

27. Failure to revert leads to accumulation of escape variant at the population level
non-B*51
non-B*51
B*51

28. Example: escape in B*51-TI8 epitope
B*51-associated I135X mutation
HIV Reverse Transcriptase

29. Increased prevalence of I135X in populations with high B*51 prevalence
% HLA-B*51 Prevalence 75 50 25 10 20
R=0.91
p=0.0006
% I135X in B*51-
Kumamoto
London
Vancouver
Perth
Oxford
Barbados
Lusaka
Durban
Gaberone
Kawashima et al, Nature 2009

30. Is it possible that HIV-1 is acting as a selective pressure on humans??

31. Vertical transmission of HIV (and genetic inheritance of HLA)
non-B*57
B*57
50% chance B*57
Mothers with protective HLA alleles less likely to transmit HIV to child
non-B*57
B*57
If B*57 improved survival
HIV-infected children who inherit protective alleles have improved chances of survival

32. 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??