1 / 32

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….

lam
Download Presentation

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

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  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??

More Related