The first T cell response to transmitted/founder virus contributes to the control of acute viremia in HIV-1 infection

Abstract

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.

Antibody‐virus co‐evolution in HIV infection: paths for HIV vaccine development

“…In individuals, HIV-1 infection is usually initiated by one or a few transmitted/founder (TF) viruses (2), and within each infected person, evolves to extraordinary diversity shaped by antibody and T cell responses (3, 4). Moreover, virus integration occurs early on in infection, before a protective antibody or T cell response can occur (5).…”

Polyvalent vaccine approaches to combat HIV‐1 diversity

“…If, as we propose, the exposure of B‐cell lineages to viral mutations that confer relative resistance is necessary to select for antibodies able to overcome that resistance, then it follows that polyvalent vaccines representing immunologically relevant epitope diversity may be essential to achieve breadth and potency. This hypothesis is supported by the in vivo development of antibody breadth, as it has been traced over years in infected subjects who are followed over time 11, 13, 68, 69. The B‐cell lineages that eventually produce bNAbs indeed start out with limited or no heterologous neutralization breadth, but can bind the autologous virus that stimulated them.…”

“…These interactions eventually drive selection of epitope variants. Importantly, epitope diversification arises in vivo prior to the development of heterologous breadth and concurrent with expansion of autologous breadth11, 13, 68, 69, 70 (also M. Bonsignori and B.F. Haynes, unpublished data). These observations, plus the general observation that serum neutralization breadth is overall slow to develop during human infection71 (see Figure 3 for an example), supports the premise that exposure to epitope diversity may be an essential aspect of the evolution of antibody breadth in vivo.…”

“…Extensive antibody and viral sequence data, as well as immunological data were collected, and this yielded a rare view of the complexities involved in the development of CD4bs bNAbs. One lineage that developed in CH505 culminated in a bNAb designated CH103, which neutralized about half of a panel of 196 viruses chosen to represent genetic and geographical diversity 11. Another lineage, designated CH235, eventually developed greater breadth and potency.…”

“…Another lineage, designated CH235, eventually developed greater breadth and potency. The unmutated germline ancestor and ancestral intermediates of these B‐cell lineages were inferred, synthesized, and their neutralization and binding sensitivity were tested against panels of autologous and heterologous Envs 11. The gains and losses in binding affinity and neutralization during bNAb ontogeny were evaluated, point mutations and insertions in Env were identified that were associated with neutralization escape, and the viral diversification was characterized as the viral quasispecies evolved in response to immune selection 11, 67…”