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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*5201-restricted T-cells, followed by targeting of the resulting escape mutant by HLA-C*1202-restricted T-cells. We further demonstrate that this phenomenon is particular to Japan, where the HLA-B*5201-C*1202 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 reve