Early Gag Immunodominance of the HIV-Specific T-Cell Response during Acute/Early Infection Is Associated with Higher CD8 ⁺ T-Cell Antiviral Activity and Correlates with Preservation of the CD4 ⁺ T-Cell Compartment

Abstract

The important role of the CD8؉ T-cell response on HIV control is well established. Moreover, the acute phase of infection represents a proper scenario to delineate the antiviral cellular functions that best correlate with control. Here, multiple functional aspects (specificity, ex vivo viral inhibitory activity [VIA] and polyfunctionality) of the HIV-specific CD8 ؉ T-cell subset arising early after infection, and their association with disease progression markers, were examined. Blood samples from 44 subjects recruited within 6 months from infection (primary HIV infection [PHI] group), 16 chronically infected subjects, 11 elite controllers (EC), and 10 healthy donors were obtained. Results indicated that, although Nef dominated the anti-HIV response during acute/early infection, a higher proportion of early anti-Gag T cells correlated with delayed progression. Polyfunctional HIV-specific CD8 ؉ T cells were detected at early time points but did not associate with virus control. Conversely, higher CD4 ؉ T-cell set points were observed in PHI subjects with higher HIV-specific CD8 ؉ T-cell VIA at baseline. Importantly, VIA levels correlated with the magnitude of the anti-Gag cellular response. The advantage of Gag-specific cells may result from their enhanced ability to mediate lysis of infected cells (evidenced by a higher capacity to degranulate and to mediate VIA) and to simultaneously produce IFN-␥. Finally, Gag immunodominance was associated with elevated plasma levels of interleukin 2 (IL-2) and macrophage inflammatory protein 1␤ (MIP-1␤). All together, this study underscores the importance of CD8 ؉ T-cell specificity in the improved control of disease progression, which was related to the capacity of Gag-specific cells to mediate both lytic and nonlytic antiviral mechanisms at early time points postinfection. Human immunodeficiency virus (HIV) still represents a major public health concern. Although the instauration of highly active antiretroviral treatment (HAART) had a tremendous impact on the epidemic dynamics, the development of an effective prophylactic vaccine is still a main objective in the HIV-related research field. As HIV is highly diverse among different isolates, evolves continuously under selective pressure, infects immune cells, and encodes proteins with the capacity to modulate immune cell functions, it imposes definite challenges that should be overcome in the race of getting a successful vaccine. However, the description of (i) infected subjects able to control HIV replication over long periods of time to very low levels without therapy (known as long-term nonprogressors [LTNP] and elite controllers [EC]); (ii) uninfected subjects who, despite being highly exposed to the virus, remain seronegative (exposed seronegatives [ESN]); and (iii) the results from the Thai vaccine trial RV-144, which showed 30% efficacy (1), suggests that the objective is reachable. In this line, much of the research work conducted over the past few years was aimed to define the immune correlates of protection, i.e....

Differential Impact of Magnitude, Polyfunctional Capacity, and Specificity of HIV-Specific CD8 + T Cell Responses on HIV Set Point

“…Our findings accord with recent data (17) showing that viral control of HIV-2 was significantly associated with a high-magnitude, polyfunctional Gag-specific CD8 ϩ T cell response. This further confirms the prevailing notion that immune responses to Gag possess enhanced antiviral potency compared to other specificities, likely as a result of its conservation and the higher rate of viral escape that exacts a fitness cost for HIV (18)(19)(20). More intriguing is the association we found with Nefspecific responses and lower VSP.…”

Ineffectual Targeting of HIV-1 Nef by Cytotoxic T Lymphocytes in Acute Infection Results in No Functional Impairment or Viremia Reduction

“…Our finding that Nef-specific CTLs have no effect on the viremia set point after acute infection is similar to recent data from Turk et al (38), but it contradicts another recent study by Riou et al, in which a correlation between polyfunctional Nef-specific CTLs and a lower viremia set point was observed (21). Similarly, there are contradictory results from recent SIV-macaque vaccine studies, some of which showed an important contribution of Nef-specific CTLs to the control of viremia (22) while others showed that Nef-specific CTLs failed to control viremia and are easily escaped from in acute infection (23,24).…”

Transcriptional and Posttranscriptional Regulation of Cytokine Gene Expression in HIV-1 Antigen-Specific CD8+T Cells That Mediate Virus Inhibition

“…We previously demonstrated that Gag-and Nefdominant soluble activity mediated by CD8 ϩ T cells during acute HIV-1 infection corresponded to the breadth of virus inhibition, as well as immune pressure against transmitted founder viruses, but that this activity was diminished by 6 months postinfection in the patients examined (6). Others have also reported early Gag and Nef CD8 ϩ T cell antiviral activity in acute infection (68,69). In addition, MIP-1␤, which correlated with inhibition in this study, correlated with initial CD8 ϩ T cell antiviral responses in acute HIV-1 infection (6) and initial viremic control (5).…”