On an individual level. Time since infection. NEJM, April HIV-1 evolution in response to immune selection pressures

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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 On an individual level. EJM, April 2008 ime since infection

2 On a global level HIV evolution in a single individual: 12 year period BD Walker, B Korber, at Immunol 2001 eg:: Shankarappa et al, J Virol 1999 HIV subtypes are differentially distributed throughout the world 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 Antigen presentation by class I viral peptide HIV-1 evolution in response to immune selection pressure by class I restricted CD8 -cells Each has a broad peptidebinding specificity HL A HL self peptide A

3 Genetic diversity in protects humans against infectious diseases CD8 -cells kill infected cells through recognition of the peptide- complex cell Receptor CD8 -cell A B C KILL IFECED CELL -A (>500 alleles) -B (>850 alleles) -C (>250 alleles) MHC displaying self peptide = no kill -restricted CL play a critical role in immune control of HIV class I alleles act as a selective force shaping viral evolution through the selection of CL escape mutations (Borrow at Med 1997, Goulder at Med 1997) plasma HIV RA (copies/ml) CD8 depletion in SIV-infected rhesus macaques results in an inability to control SIV viremia HIV-specific CL (Matano JVI 1998; Schmitz, Science 1999; Jin JEM 1999) Certain alleles are associated with better HIV disease outcomes (i.e., B*27) (Carrington, Science 1999; Migueles, PAS 2000; Gao, at Med 2005) CL? Escape mutations allow CL HIV escape to evade pathways are predictable based on host recognition by - Moore et al Science 2002 cells Allen et al J Virol 2004 Draenert et al JEM 2006 Brumme et al PLoS Pathogens 2007 Koup, JVI 1994; Borrow, JVI 1994; Borrow, at Med 1997 Days/weeks months years Escape mutations abrogate peptide- binding Mapping sites of immune escape across the HIV-1 genome Pt1:..SLQEQIGW.. + Pt2:..SLQEQIGW.. - Pt3:..SLQEQIGW.. + Pt4:..SLQEQIGW.. - Pt5:..SLQEQIGW.. - Pt6:..SLQEQIAW.. + Pt7:..SLQEQIW.. - Pt8:..SLQEQIGW p = 0.03

4 Problem: Simple method ignores phylogenetic structure of the data Scenario 1 Here, the tree helps explain the data. Simple method over overestimatesestimates the correlation. Scenario 1 Scenario 2 International HIV Adaptation Collaborative (IHAC) vs. ow, the data is surprising in light of the tree. Simple method under underestimatesestimates the correlation. Cohort: from Analysis: Cross-sectional analysis of ~1500 chronicallysubtype B infected, treatment naive subjects Canada, the USA and Australia Identify -associated polymorphisms using phylogenetically-informed methods >1000 unique associated polymorphisms in Gag, Pol, ef GAG: 338 associations at 108 codons Gag: Immune escape map POL: 248 associations at 78 codons EF: 499 associations at 99 codons association Susceptible Adapted

5 Gag: Gag: Immune escape map Immune escape map ransmission and reversion of escape mutations non non Are escape mutations in HIV-1 accumulating at the population level? selection Failure to revert leads to accumulation of escape variant at the population level nonb*51 B*51 reversion Example: escape in B*51-I8 epitope nonb*51 B*51-associated I135X mutation HIV Reverse ranscriptase

6 Increased prevalence of I135X in populations with high B*51 prevalence 75 Kumamoto R=0.91 p= % I135X in B* Gaberone London Perth Vancouver Barbados Is it possible that HIV-1 is acting as a selective pressure on humans?? Durban Oxford Lusaka % -B*51 Prevalence Kawashima et al, ature 2009 Vertical transmission of HIV (and genetic inheritance of ) Mothers with protective alleles less likely to transmit HIV to child non- HIV-infected children who inherit protective alleles have improved chances of survival non- Differential survival rates associated with HIV infection and/or carriage of protective alleles could cause changes in prevalence of specific alleles in human populations over time his may be especially relevant in areas where HIV prevalence is very high 50% chance If improved survival HIV infection could be acting as a selective force shaping human evolution Summary and Conclusions - Strong evidence of -associated immune selection on HIV - HIV Immune escape pathways are broadly predictable based on host - 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??