Conserved HIV-1 Gag p24 Epitopes Elicit Cellular Immune Responses That Impact Disease Outcome.

Abstract

Although the breadth of the human immunodeficiency virus type 1 (HIV-1)-specific cellular immune response and its impact on the control of viral replication have already been addressed, reported data have proven controversial. We hypothesize that the nature of targeted epitopes, rather than the simple breadth or magnitude of responses, correlates with disease outcome. In this study, we explore the occurrence of patterns of Gag p24 recognition among untreated HIV-1-infected patients by identifying the epitopes that compose such patterns and how they distinctly associate with disease progression. Utilizing enzyme-linked immunospot (ELISPOT) interferon gamma (IFN-γ), we screened cellular responses of 27 HIV-1-infected subjects against 15-mer peptides encompassing the whole Gag p24 protein. Obtained data were used to develop a clustering analysis that allowed definition of two groups of individuals with totally distinct patterns of recognition. Although targeted Gag p24 peptides were completely different between the two groups, the breadth and magnitude of the responses were not. Interestingly, viral control and preservation of CD4+ T cells were increased in one group. In addition, we compared genetic conservation of amino acid sequences of the recognized peptides, as well as of the human leucocyte antigen class I (HLA-I)-restricted epitopes within them. Subjects presenting higher control of HIV-1 replication targeted more conserved epitopes, and higher genetic variation was present mainly in anchor residues for HLA-I molecules. We strengthen the existing evidence from cases of HIV-1 infection in humans that, cellular immune responses targeting conserved epitopes, rather than the magnitude and breadth of responses, associate with a better control of viral replication and maintenance of peripheral CD4+ T cell counts.