Carlson, Jonathan M.Du, Victor Y.Pfeifer, NicoBansal, AnjuTan, Vincent Y.F.Power, KarenBrumme, Chanson J.Kreimer, AnatDeZiel, Charles E.Fusi, NicoloSchaefer, MalindaBrockman, Mark A.Gilmour, JillPrice, Matt A.Kilembe, WilliamHaubrich, RichardJohn, MinaMallal, SimonShapiro, RogerFrater, JohnHarrigan, P. RichardNdung’u, ThumbiAllen, SusanHeckerman, DavidSidney, JohnAllen, ToddGoulder, Philip J.R.Brumme, Zabrina L.Hunter, EricGoepfert, Paul A.2016-12-022016Carlson, J. M., V. Y. Du, N. Pfeifer, A. Bansal, V. Y. Tan, K. Power, C. J. Brumme, et al. 2016. “Impact of Pre-adapted HIV Transmission.” Nature medicine 22 (6): 606-613. doi:10.1038/nm.4100. http://dx.doi.org/10.1038/nm.4100.1078-8956http://nrs.harvard.edu/urn-3:HUL.InstRepos:29626042Human Leukocyte Antigen class I (HLA) restricted CD8+ T lymphocyte (CTL) responses are critical to HIV-1 control. Although HIV can evade these responses, the longer-term impact of viral escape mutants remains unclear, since these variants can also reduce intrinsic viral fitness. To address this question, we here develop a metric to determine the degree of HIV adaptation to an HLA profile. We demonstrate that transmission of viruses pre-adapted to the HLA molecules expressed in the recipient is associated with impaired immunogenicity, elevated viral load and accelerated CD4 decline. Furthermore, the extent of pre-adaptation among circulating viruses explains much of the variation in outcomes attributed to expression of certain HLA alleles. Thus, viral pre-adaptation exploits “holes” in the immune response. Accounting for these holes may be critical for vaccine strategies seeking to elicit functional responses from viral variants, and to HIV cure strategies requiring broad CTL responses to achieve successful eradication of HIV reservoirs.en-USJournal Article2016-12-0210.1038/nm.4100