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HIV-1 evolution in response to immune selection pressures BISC 441 guest lecture

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….

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HIV-1 evolution in response to immune selection pressures BISC 441 guest lecture

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  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

  2. http://www3.niaid.nih.gov/topics/HIVAIDS/Understanding/Biology/structure.htmhttp://www3.niaid.nih.gov/topics/HIVAIDS/Understanding/Biology/structure.htm

  3. On an individual level…. Time since infection

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

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

  6. HIV subtypes are differentially distributed throughout the world http://www.hiv.lanl.gov

  7. 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

  8. 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!

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

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

  11. 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

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

  13. 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

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

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

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

  17. 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

  18. 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

  19. * 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

  20. T N 0 4 B*57 p = 0.03 4 0 not B*57 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

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

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

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

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

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

  26. R=0.91 p=0.0006 75 Kumamoto 50 London % I135X in B*51- Perth Vancouver Gaberone 25 Barbados Oxford Durban Lusaka 0 10 20 % HLA-B*51 Prevalence Increased prevalence of I135X in populations with high B*51 prevalence Kawashima et al, Nature 2009

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

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

  29. 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??

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