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.On sexual transmission, HIV-1 infects CD4
+CCR5
+ T cells and remains localized in genital/rectal mucosa and draining lymph nodes for ∼10 d (
1). Virus then spreads via the blood to other lymphoid tissue, especially that in the gut (
2). There, it replicates profusely and the level of free virus in the blood rises exponentially to reach a peak, often millions of virus copies per milliliter of plasma, 21–28 d after infection. Virus level then falls, rapidly at first, until a stable level is reached (
3,
4). This set point varies across patients and is partially predictive of the later course of disease in the absence of antiretroviral drugs; patients with low set points progress to AIDS more slowly (
5).It is uncertain how the peak viremia of acute HIV-1 infection is controlled. Some mathematical models (
6–
8) suggest that the rampant early infection simply destroys so many CD4 T cells in the gut (
2,
9) and elsewhere that the cell substrate becomes limiting. However, reduction of peak viremia in rhesus macaques infected with simian immunodeficiency virus (SIV) was dependent on the presence of CD8 cells (
10), either T or NK cells, or both. In HIV-1 infection, virus-specific CD8 T cells first appear in the blood just before the viremia peaks and then expand and contract as virus load falls (
11–
13). HIV-1–specific CD8 T cells are detectable before seroconversion and long before neutralizing antibodies (NAbs) (
14). However, the mere presence of such T cells does not prove that they control virus. Indirect evidence for their importance comes from HLA class I allelic associations with low virus set point and with delayed progression to AIDS (
15), but these effects, which are probably mediated by HLA class I–restricted T cells, could occur after the initial drop in viremia. Overall, this leaves the relative importance of CD8 T cells and the loss of infectable target cells to the decline of viremia of acute HIV-1 infection unresolved.Further clues for a role of CD8 T cells in HIV-1 containment comes from studies demonstrating that they select virus escape mutations as early as 30–54 d after the peak viremia of acute infection (
16,
17) and continue to select mutations throughout chronic infection (
18–
26). Nearly all these observations have been made after the steep decline from peak viremia, as the virus is stabilizing at its set point, or later. Few studies have directly measured T cell escape; it is more often argued that changes in virus sequence in regions that correspond to CD8 T cell epitopes matching the HLA type of the patient are selected by T cells (e.g., see reference
28). However, this approach can be confounded by the many overlapping epitopes, that are presented by different HLA types (
27). Approaches based on sequence alone also miss T cell responses to invariant epitopes as well as mutants selected by other immune responses.In this paper, a comprehensive study was made of the ontogeny of the primary T cell response in acute HIV-1 infection. The single genome amplification (SGA) sequencing technique (
28,
29) identified the single transmitted/founder virus sequence in each of four preseroconversion patients, before the immune response had made a discernable imprint on the virus quasispecies. The adaptive immune responses to the transmitted virus proteome were then followed using peptides matched to autologous founder virus and to subsequent mutants, to capture responses that might otherwise be missed because of virus variability (
30). This approach identified the first T cell responses in HIV-1–infected humans and showed that virus escape mutants were rapidly selected as viremia fell from its peak in acute infection. A mathematical model quantified the downward pressure exerted by these CD8 T cell responses on the virus, showing that they contributed to the concurrent reduction of viremia. These data imply that vaccines that stimulate strong and broad early CD8 T cell responses to HIV-1 should be valuable.
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