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¹ Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, Oxford University, Oxford OX3 9DS, England, UK
² Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294
³ Duke University Medical Research, Duke University, Durham, NC 27710
⁴ Los Alamos National Laboratory, Theoretical Division, Los Alamos, NM 87545
⁵ The Jenner Institute, Oxford University, Compton RG20 7NN, England, UK
⁶ BIDMC, Harvard University, Boston, MA 02115
⁷ HIV Prevention Trials Unit, University of North Carolina, Chapel Hill, NC 27599
⁸ The Santa Fe Institute, Santa Fe, NM 87501

CORRESPONDENCE Andrew J. McMichael: andrew.mcmichael{at}imm.ox.ac.uk

Identification of the transmitted/founder virus makes possible, for the first time, a genome-wide analysis of host immune responses against the infecting HIV-1 proteome. A complete dissection was made of the primary HIV-1–specific T cell response induced in three acutely infected patients. Cellular assays, together with new algorithms which identify sites of positive selection in the virus genome, showed that primary HIV-1–specific T cells rapidly select escape mutations concurrent with falling virus load in acute infection. Kinetic analysis and mathematical modeling of virus immune escape showed that the contribution of CD8 T cell–mediated killing of productively infected cells was earlier and much greater than previously recognized and that it contributed to the initial decline of plasma virus in acute infection. After virus escape, these first T cell responses often rapidly waned, leaving or being succeeded by T cell responses to epitopes which escaped more slowly or were invariant. These latter responses are likely to be important in maintaining the already established virus set point. In addition to mutations selected by T cells, there were other selected regions that accrued mutations more gradually but were not associated with a T cell response. These included clusters of mutations in envelope that were targeted by NAbs, a few isolated sites that reverted to the consensus sequence, and bystander mutations in linkage with T cell–driven escape.

Abbreviations used: FEL, fixed-effects likelihood; ICS, intracellular cytokine staining; NAb, neutralizing antibody; SFU, spot forming unit; SGA, single genome amplification; SIV, simian immunodeficiency virus.

© 2009 Goonetilleke et al.
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