In Chronic Infection, HIV Gag-Specific CD4 + T Cell Receptor Diversity Is Higher than CD8 + T Cell Receptor Diversity and Is Associated with Less HIV Quasispecies Diversity

Cellular immune responses to Gag correlate with improved HIV control. The full extent of cellular immune responses comprises both the number of epitopes recognized by CD4(+) and CD8(+) T cells and the diversity of the T cell receptor (TCR) repertoire directed against each epitope. The optimal diversity of the responsive TCR repertoire is unclear. Therefore, we evaluated the TCR diversity of CD4(+) and CD8(+) T cells responding to HIV-1 Gag to determine if TCR diversity correlates with clinical or virologic metrics. Previous studies of TCR repertoires have been limited primarily to CD8(+) T cell responses directed against a small number of well-characterized T cell epitopes restricted by specific human leukocyte antigens. We stimulated peripheral blood mononuclear cells from 21 chronic HIV-infected individuals overnight with a pool of HIV-1 Gag peptides, followed by sorting of activated CD4(+) and CD8(+) T cells and TCR deep sequencing. We found Gag-reactive CD8(+) T cells to be more oligoclonal, with a few dominant TCRs comprising the bulk of the repertoire, compared with the highly diverse TCR repertoires of Gag-reactive CD4(+) T cells. HIV sequencing of the same donors revealed that high CD4(+) T cell TCR diversity was strongly associated with lower HIV Gag genetic diversity. We conclude that the TCR repertoire of Gag-reactive CD4(+) T helper cells displays substantial diversity without a clearly dominant circulating TCR clonotype, in contrast to a hierarchy of dominant TCR clonotypes in the Gag-reactive CD8(+) T cells, and may serve to limit HIV diversity during chronic infection. IMPORTANCE Human T cells recognize portions of viral proteins bound to host molecules (human leukocyte antigens) on the surface of infected cells. T cells recognize these foreign proteins through their T cell receptors (TCRs), which are formed by the assortment of several available V, D, and J genes to create millions of combinations of unique TCRs. We measured the diversity of T cells responding to the HIV Gag protein. We found that the CD8(+) T cell response is primarily made up of a few dominant unique TCRs, whereas the CD4(+) T cell subset has a much more diverse repertoire of TCRs. We also found there was less change in the virus sequences in subjects with more diverse TCR repertoires. HIV has a high mutation rate, which allows it to evade the immune response. Our findings describe the characteristics of a virus-specific T cell response that may allow it to limit viral evolution.