Vertical T cell immunodominance and epitope entropy determine HIV-1 escape

Abstract

HIV-1 accumulates mutations in and around reactive epitopes to escape recognition and killing by CD8 + T cells.Measurements of HIV-1 time to escape should therefore provide information on which parameters are most important for T cell-mediated in vivo control of HIV-1. Primary HIV-1-specific T cell responses were fully mapped in 17 individuals, and the time to virus escape, which ranged from days to years, was measured for each epitope. While higher magnitude of an individual T cell response was associated with more rapid escape, the most significant T cell measure was its relative immunodominance measured in acute infection. This identified subject-level or "vertical" immunodominance as the primary determinant of in vivo CD8 + T cell pressure in HIV-1 infection. Conversely, escape was slowed significantly by lower population variability, or entropy, of the epitope targeted. Immunodominance and epitope entropy combined to explain half of all the variability in time to escape. These data explain how CD8 + T cells can exert significant and sustained HIV-1 pressure even when escape is very slow and that within an individual, the impacts of other T cell factors on HIV-1 escape should be considered in the context of immunodominance.

Polyvalent vaccine approaches to combat HIV‐1 diversity

“…Thus, VRC01 comes into close contact with both conserved and extremely variable regions of Env, and yet VRC01 maintains great breadth and potency. We argue that mutations in the high diversity regions in Env drive autologous immune escape in vivo, and that this is an essential component of the factors that collectively induce neutralization breadth 13, 67. The same holds for other CD4bs bNAbs, as well as other bNAb classes.…”

“…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.…”

“…The outcome for both antibody and virus is driven by the frequencies of their variant forms in the population, their relative levels of affinity, and the antibody's functional capacity to counteract and select against viral variants. When intensive longitudinal sampling was undertaken, “cooperative” autologous neutralizing antibody lineages were observed13 (M. Bonsignori and B.F. Haynes, unpublished data), adding a further dimension of complexity to this system. In these studies, it was shown that escape from one B‐cell lineage can lead to developing sensitivity to another, and the development of neutralizing antibody breadth was facilitated by these interactions.…”

“…B cells are then selected that can still bind the resistant viruses, and these interactions lead to enhanced heterologous neutralization breadth, as many of these same antibody‐resistance mutations are found in the heterologous virus population. In this view, bNAb lineages start with limited neutralization breadth, which increases as they are selected for their ability to tolerate epitope variation, by exposure to the diversity that arises as a consequence of continuous cycles of autologous immune escape and selection for recognition 13. If these mutations do not reduce viral fitness, and if the respective epitopes are commonly targeted, then the sampled escape mutations will be reflected in the diversity found at the population level.…”

“…High baseline rates of HIV‐1 mutation6 and replication7 lay a foundation of viral diversity, and this combined with continuous immune‐driven selection generates a complex and unique viral quasispecies in each infected person 8, 9, 10, 11, 12. An extensive range of mutations and combinations of mutations, even within single epitopes, can be explored by the virus in response to immune pressures,8, 9, 13 and the delicate balance of immune escape and replicative fitness shifts over time as other mutations, sometimes compensatory, come into play 14. Successful ART constrains this dynamic, although the extent to which the virus continues to replicate during ART is still not fully resolved 15.…”