Antiretroviral Therapy Reduces the Magnitude and T Cell Receptor Repertoire Diversity of HIV-Specific T Cell Responses without Changing T Cell Clonotype Dominance

Abstract

After initiation of antiretroviral therapy (ART), HIV loads and frequencies of HIV epitope-specific immune responses decrease.A diverse virus-specific T cell receptor (TCR) repertoire allows the host to respond to viral epitope diversity, but the effect of antigen reduction as a result of ART on the TCR repertoire of epitope-specific CD8 ؉ T cell populations has not been well defined. We determined the TCR repertoires of 14 HIV-specific CD8 ؉ T cell responses from 8 HIV-positive individuals before and after initiation of ART. We used multiparameter flow cytometry to measure the distribution of memory T cell subsets and the surface expression of PD-1 on T cell populations and T cell clonotypes within epitope-specific responses from these individuals. Post-ART, we noted decreases in the frequency of circulating epitope-specific T cells (P ‫؍‬ 0.02), decreases in the number of T-cell clonotypes found within epitope-specific T cell receptor repertoires (P ‫؍‬ 0.024), and an overall reduction in the amino acid diversity within these responses (P < 0.0001). Despite this narrowing of the T cell response to HIV, the overall hierarchy of dominant T cell receptor clonotypes remained stable compared to that pre-ART. CD8؉ T cells underwent redistributions in memory phenotypes and a reduction in CD38 and PD-1 expression post-ART. Despite extensive remodeling at the structural and phenotypic levels, PD-1 was expressed at higher levels on dominant clonotypes within epitope-specific responses before and after initiation of ART. These data suggest that the antigen burden may maintain TCR diversity and that dominant clonotypes are sensitive to antigen even after dramatic reductions after initiation of ART.

Virological Control by the CD4-Binding Site Antibody N6 in Simian-Human Immunodeficiency Virus-Infected Rhesus Monkeys

“…In this study, we did detect increased autologous nAb titers, but this was independent of bnAb treatment and most likely a function of extended viral exposure in these chronically infected animals. In contrast, SHIV-specific CD8 ϩ T-cell frequencies significantly declined in animals that had received bnAbs, most likely due to memory cell contraction in the setting of reduced antigen, as has been described for patients on antiretroviral therapy (ART) (36). It should be noted that the duration of antibody therapy in this model is brief, due to the potential for cross-species immune responses to the passively administered antibody.…”

HIV-specific CD8+ T cells and HIV eradication

“…This exhausted state is associated with the upregulation of multiple activation and coinhibitory molecules (see below) (49)(50)(51)(52)(53)(54)(55). Several studies have demonstrated that prolonged ARV therapy results in some restoration of polyfunctionality and at least partial downregulation of activation and exhaustion markers (49)(50)(51)(52)(56)(57)(58)(59)(60). It is tempting to speculate that, despite being reduced in numbers, the HIV-specific CD8 + T cells that remain in ARV-treated subjects may be more functional, less restrained by coinhibition, and less proapoptotic.…”

Preserving HIV-specific T cell responses

“…With declining levels of plasma viremia and subsequent suppression, levels of Gag-specific and Pol-specific CTL precursors decrease and these correlate with decreased CD8 + IFNγ responses [62]. Not only is there a decrease in the frequency of epitope-specific T cells, but also in the number of T cell clonotypes within epitope-specific T cell repertoires [63]. With declining plasma viremia on ART, CD4 + T cell frequencies increase in blood and gut mucosal tissue within the first 9 months after starting ART [64 ▪ ].…”