Targeting of Conserved Gag-Epitopes in Early HIV Infection Is Associated with Lower Plasma Viral Load and Slower CD4⁺T Cell Depletion

Abstract

We aimed to investigate whether the character of the immunodominant HIV-Gag peptide (variable or conserved) targeted by CD8(+) T cells in early HIV infection would influence the quality and quantity of T cell responses, and whether this would affect the rate of disease progression. Treatment-naive HIV-infected study subjects within the OPTIONS cohort at the University of California, San Francisco, were monitored from an estimated 44 days postinfection for up to 6 years. CD8(+) T cells responses targeting HLA-matched HIV-Gag-epitopes were identified and characterized by multicolor flow cytometry. The autologous HIV gag sequences were obtained. We demonstrate that patients targeting a conserved HIV-Gag-epitope in early infection maintained their epitope-specific CD8(+) T cell response throughout the study period. Patients targeting a variable epitope showed decreased immune responses over time, although there was no limitation of the functional profile, and they were likely to target additional variable epitopes. Maintained immune responses to conserved epitopes were associated with no or limited sequence evolution within the targeted epitope. Patients with immune responses targeting conserved epitopes had a significantly lower median viral load over time compared to patients with responses targeting a variable epitope (0.63 log(10) difference). Furthermore, the rate of CD4(+) T cell decline was slower for subjects targeting a conserved epitope (0.85% per month) compared to subjects targeting a variable epitope (1.85% per month). Previous studies have shown that targeting of antigens based on specific HLA types is associated with a better disease course. In this study we show that categorizing epitopes based on their variability is associated with clinical outcome.

Broad and persistent Gag-specific CD8+ T-cell responses are associated with viral control but rarely drive viral escape during primary HIV-1 infection

“…Our findings provide a clear demonstration of the broadening of Gag–specific T-cell responses over the course of one year following HIV-1 infection, with this increased immunogenicity associated with lower viral load set point. Our findings are in line with other studies, which have shown that the presence of a high proportion of Gag-specific CD8+ T-cell responses correlates with delayed disease progression [19–21, 23, 46–48]. …”

“…Interestingly, participants with persisting detectable T-cell responses against invariant epitopes, had significantly lower viral load set point values when compared to participants with responses to epitopes containing variant sequences but subsequently lost these responses. These data suggest that persisting Gag-specific T-cell responses, which may be the result of continual invariant viral epitope presentation or the generation of de novo responses to arising variant epitopes, bear the greatest burden on control of early HIV-1 replication and disease progression [19, 24, 49]. …”

“…Although numerous studies have examined CD8+ T-cells in early infection [1, 2, 8, 11, 21, 23–28], less is known about the impact and fate these responses in persons with clearly defined dates of infection in whom studies have been initiated within a month of exposure to the virus [3, 7, 11, 13, 21, 24, 29]. A number of studies have reported on the longitudinal analysis of CD8+ T-cell responses in relation to time from initial acute or primary infection and viral load, in order to determine the kinetics and fate of these responses and their impact on the virus over time [3, 5, 13, 19, 21–24, 30]. However, few have assessed CD8+ T-cells to the entire viral proteome during acute infection and at one year in antiretroviral-naïve persons, in high prevalence and incidence settings [5, 24].…”

Effective Cytotoxic T Lymphocyte Targeting of Persistent HIV-1 during Antiretroviral Therapy Requires Priming of Naive CD8 + T Cells

“…Important interplay between protein conservation in HIV-1 and immune targeting has been postulated ( 44 ), including the possibility that immunodominance benefits viral persistence ( 45 ) by preferentially exposing mutable epitopes. It has additionally been suggested that targeting conserved, lower-entropy regions of gag could be associated with a clinical benefit ( 46 ), particularly when targeting the latent HIV-1 reservoir ( 9 ). The primary epitope targeting described here raised the intriguing possibility that the new set of epitopes would be qualitatively different in terms of their conservation.…”

Development of gold nanoparticle-based antigen delivery platform for vaccines against HIV-1

“…T cell activity from these studies highlighted the usage of the Gag protein or its components as vaccine candidates. The T cell epitopes on Gag has already been identified [275], with one study reporting that patients whose immune responses targeted the conserved HIV-Gag-epitopes had significantly lower viral load compared to those targeting variable epitopes [276]. For our study, the conserved T cell epitope of Gag protein will be selected to load inside the GNCs to eliciting cell-mediated immunity.…”