T-Cell Responses To Sequentially Emerging Viral Escape Mutants Shape Long-Term Hiv-1 Population Dynamics

HIV-1 strains harboring immune escape mutations can persist in circulation, but the impact of selection by multiple HLA alleles on population HIV-1 dynamics remains unclear. In Japan, HIV-1 Reverse Transcriptase codon 135 (RT135) is under strong immune pressure by HLA-B*51:01-restricted and HLA-B*52:01-restricted T cells that target a key epitope in this region (TI8; spanning RT codons 128-135). Major population-level shifts have occurred at HIV-1 RT135 during the Japanese epidemic, which first affected hemophiliacs (via imported contaminated blood products) and subsequently non-hemophiliacs (via domestic transmission). Specifically, threonine accumulated at RT135 (RT135T) in hemophiliac and non-hemophiliac HLA-B*51:01(+) individuals diagnosed before 1997, but since then RT135T has markedly declined while RT135L has increased among non-hemophiliac individuals. We demonstrated that RT135V selection by HLA-B*52:01-restricted TI8-specific T-cells led to the creation of a new HLA-C*12:02-restricted epitope TN9-8V. We further showed that TN9-8V-specific HLA-C*12:02-restricted T cells selected RT135L while TN9-8T-specific HLA-C*12:02-restricted T cells suppressed replication of the RT135T variant. Thus, population-level accumulation of the RT135L mutation over time in Japan can be explained by initial targeting of the TI8 epitope by HLA-B*52:01-restricted T-cells, followed by targeting of the resulting escape mutant by HLA-C*12:02-restricted T-cells. We further demonstrate that this phenomenon is particular to Japan, where the HLA-B*52:01-C*12:02 haplotype is common: RT135L did not accumulate over a 15-year longitudinal analysis of HIV sequences in British Columbia, Canada, where this haplotype is rare. Together, our observations reveal that T-cell responses to sequentially emerging viral escape mutants can shape long-term HIV-1 population dynamics in a host population-specific manner.Author summaryHIV-1 strains harboring immune escape mutations can accumulate in circulation, but it remains unclear to what extent these 'escaped' HIV-1 strains continue to evolve under ongoing population-level immune pressures. We investigated population-level changes at HIV-1 Reverse Transcriptase codon 135 (RT135), which is under pressure by T cells restricted by HLA-B*51:01 and B*52:01, highly frequent alleles in Japan. While threonine initially accumulated at RT135, RT135L has subsequently increased markedly. Our findings revealed that RT135V selection by HLA-B*52:01-restricted T-cells led to the creation of a new epitope restricted by HLA-C*12:02, an allele in strong linkage disequilibrium with HLA-B*52:01. HLA-C*12:02-restricted T cells in turn suppressed replication of RT135T virus and selected RT135L. Notably, population-level shifts at this codon are particular to Japan, where HLA-B*52:01-C*12:02 represents the most prevalent HLA haplotype. Our findings highlight multiple virus-specific T cells as dynamic drivers of population-level - and host population-specific - HIV-1 evolution over the long term.