Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
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??