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

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.

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 anti-HIV 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 CTL HLA

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”

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

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

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

* * * * 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

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

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 non-B*57 non-B*57 reversion B*57 selection

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

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

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

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??