Population-level spread of immune-driven mutations in HIV-1 Polymerase during the North American epidemic Natalie Kinloch - Simon Fraser University Tuesday, July 21 st, 2015 CTL escape reproducible based on host HLA CTL escape variants selected selection reproducible based on host HLA profile response HLA-restricted Carlson et al. (2014). Trends Microbiol. Reversion Persistence Transmission of escape mutations and the implications of reversion and persistence Reversion Persistence Transmission of escape mutations and the implications of reversion and persistence Objective investigate extent and consequences of HLA- associated polymorphism accumulation in HIV-1 Polymerase gene over the course of the epidemic in North America PRRTINT Historic ( ) and Modern ( ) N= ~300/ cohort key epidemic cities: Vancouver, Boston, New York, San Francisco linked HIV-1 Polymerase/ Host HLA class I data well-matched for HLA class I allele frequency Most Recent Common Ancestor ~ 1968 founder HIV virus Vancouver San Francisco New York Boston Historic and Modern Cohorts HLA-driven diversification of epidemic 2-fold diversification of epidemic between historic and modern eras diversifying sites enriched for HLA-associated codons HistoricModern 2.6-fold increase in HLA-associated polymorphism frequency between eras compare frequency between historic and modern cohorts individuals lacking selecting allele some increasing in frequency, others stable Phylogenetic analysis determines pre-1979 sequences ~ Time 1979 Phylogenetic analysis supports polymorphism spread determine polymorphism frequency between: MRCA reconstructed ancestors historic cohort modern cohort sequences median frequency increases over time Greatest relative spread of polymorphisms observed in protective alleles Published Escape Mutations A*02:011L A*11:012V A*32:013L B*51:014Y B*13:025P B*40:015T B*27:057H C*02:018I C*06:029A C*17:0111T HLA class I Alleles A*02:01 A*32:01 B*51:01 B*40:01 C*06:02 C*17:01 Then vs. Now: How pre-adapted is the average circulating sequence to us? Published Escape Mutations A*02:011L A*11:012V A*32:013L B*51:014Y B*13:025P B*40:015T B*27:057H C*02:018I C*06:029A C*17:0111T HLA class I Alleles A*02:01 A*32:01 B*51:01 B*40:01 C*06:02 C*17:01 Then vs. Now: How pre-adapted is the average circulating sequence to us? 5 HLA- Associated Sites = Host #1 Published Escape Mutations A*02:011L A*11:012V A*32:013L B*51:014Y B*13:025P B*40:015T B*27:057H C*02:018I C*06:029A C*17:0111T HLA class I Alleles A*02:01 A*32:01 B*51:01 B*40:01 C*06:02 C*17:01 Then vs. Now: How pre-adapted is the average circulating sequence to us? 5 HLA- Associated Sites = PQLYLWQRPLV =2/5 Median Escaped Sites: =1/5 =20% Then vs. Now: How pre-adapted is the average circulating sequence to us? =1/5 PQITLWQRPLV PQLTLWQRPLV PQITLWQRPLT PQITLWQRPLV PQLYLWQRPLV PQITLWQRALV PQITLWQRPLV PQLTLWQRALV =2/5 =1/5 =0/5 =1/5 =0/5 =1/5 Host #1- Historic Sequences PQLTLWQRALT =1/5 Median Escaped Sites: =1/5 =20% Then vs. Now: How pre-adapted is the average circulating sequence to us? =1/5 PQITLWQRPLV PQLTLWQRPLV PQITLWQRPLT PQITLWQRPLV PQLYLWQRPLV PQITLWQRALV PQITLWQRPLV PQITLWQRALV =2/5 =1/5 =0/5 =1/5 =0/5 =1/5 PQITLWQRALT =1/5 Median Escaped Sites: =2/5 =40% Host #1- Modern Sequences =2/5 PQITLWQRPLV PQLTLWQRPLV PQITLWQRALT PQITLWQRPLV PQLYLWQRPLV PQITLWQRALT PQITLWQRPLV PQIYLWQRALV =2/5 =0/5 =2/5 =0/5 =1/5 PQLTLWQRALT =2/5 Host #1- Historic Sequences Sequence pre-adaptation to host low, but increasing pre-adaptation of MRCA, average circulating ancestrally reconstructed, historic, and modern sequences to hosts Majority =0%, regardless of era higher levels of pre- adaptation increasing with time Conclusions HIV-1 Polymerase diversified roughly 2-fold since 1979 in North America 2.6-fold relative increase in polymorphism frequency between historic and modern eras average modern circulating sequence 0% pre- adapted to the majority of hosts however, proportion of sequences carrying higher levels of pre-adaptation increasing over time Acknowledgements Zabrina Brumme Daniel MacMillan Anh Le Laura Cotton Brumme/Brockman Lab Members Jonathan Carlson Art Poon Rosemary McCloskey Richard Liang David Bangsberg Susan Buchbinder Mary Carrington Jonathan Fuchs Beryl Koblin Martin Markowitz Kenneth Mayer M.J. Milloy Martin Schechter Theresa Wagner Richard Harrigan Bruce Walker