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

Abstract

Objective We characterized protein-specific CD8+ T-cell immunodominance patterns during the first year of HIV-1 infection, and their impact on viral evolution and immune control. Methods We analyzed CD8+ T-cell responses to the full HIV-1 proteome during the first year of infection in eighteen antiretroviral-naïve individuals with acute HIV-1 subtype C infection, all identified prior to seroconversion. Ex vivo and cultured IFN-γ ELISPOT assays were performed and viruses from plasma were sequenced within defined CTL Gag epitopes. Results Nef-specific CD8+ T-cell responses were dominant during the first 4 weeks post infection and made up 40% of total responses at this time, yet by 1 year responses against this region had declined and Gag responses made up to 47% of all T-cell responses measured. An inverse correlation between the breadth of Gag-specific responses and viral load set point was evident at 26 weeks post infection (p=0.0081; r= −0.60) and beyond. An inverse correlation between the number of persistent responses targeting Gag and viral set point was also identified (p=0.01; r=−0.58). Gag-specific responses detectable by the cultured ELISPOT assay correlated negatively with viral load set point (p=0.0013; r=−0.91). Sequence evolution in targeted and non-targeted Gag epitopes in this cohort was infrequent. Conclusions These data underscore the importance of HIV-specific CD8+ T-cell responses, particularly to the Gag protein, in the maintenance of low viral load levels during primary infection and show that these responses are initially poorly elicited by natural infection. These data have implications for vaccine design strategies.

What do mathematical models tell us about killing rates during HIV-1 infection?

“…As a result, the selective advantage for the virus to escape just one CTL response decreases [41], leading to slow escape. Consistent with this, a recent study showed that broad Gag responses are associated with few escapes and low viral load in HIV-1-infected individuals [42]. Thus, slow escape rates during chronic infections are to be expected for broad immune responses, and are not indicative of non-lytic or poor control by CTLs.…”

Monitoring Integration over Time Supports a Role for Cytotoxic T Lymphocytes and Ongoing Replication as Determinants of Reservoir Size

“…Several mechanisms may be responsible for the greater reduction in primary infection. One possible explanation is the lack of escape CTL in the very early stage of infection (40,41). As recently reported by Deng and colleagues (41), CTL escape variants dominate the HIV reservoir of individuals starting ART during chronic but not acute infection; moreover, these CTL escape variants can be reactivated and released after latency reversal.…”

“…In addition, CTL may be more functional early in infection (40,42). Several studies have investigated the functional profile of CD8 T cells during primary infection.…”

Diversity and divergence of the glioma-infiltrating T-cell receptor repertoire

“…The repertoire-wide property H Δ , as a measure of the component of CDR3 diversity most closely tied to antigen binding function, facilitates quantitative comparison between TCR repertoires. Here, we observed increasing VJ-independent diversity in the TIL repertoires-but not the matched PBMC-of patients with increasing glioma grade, suggestive of the diversified antigen targeting associated with active T-cell responses in both cancer and infectious diseases (24)(25)(26).…”