Induction of Gag-Specific CD4 T Cell Responses during Acute HIV Infection Is Associated with Improved Viral Control

Abstract

Effector CD4 T cell responses have been shown to be critically involved in the containment and clearance of viral pathogens. However, their involvement in the pathogenesis of HIV infection is less clear, given their additional role as preferred viral targets. We previously demonstrated that the presence of HIV-specific CD4 T cell responses is somewhat associated with HIV control and that specific CD4 T cell functions, such as direct cytolytic activity, can contribute to control of HIV viremia. However, little is known about how the induction of HIV-specific CD4 T cell responses during acute HIV infection influences disease progression and whether responses induced during the early phase of infection are preferentially depleted. We therefore longitudinally assessed, in a cohort of 55 acutely HIV-infected individuals, HIV-specific CD4 T cell responses from acute to chronic infection. Interestingly, we found that the breadth, magnitude, and protein dominance of HIV-specific CD4 T cell responses remained remarkably stable over time. Moreover, we found that the epitopes targeted at a high frequency in acute HIV infection were recognized at the same frequency by HIV-specific CD4 T cells in chronic HIV infection. Interestingly the induction of Gagspecific CD4 T cell responses in acute HIV infection was significantly inversely correlated with viral set point in chronic HIV infection (R ‫؍‬ ؊0.5; P ‫؍‬ 0.03), while the cumulative contribution of Env-specific CD4 T cell responses showed the reverse effect. Moreover, individuals with HIV-specific CD4 T cell responses dominantly targeting Gag over Env in acute HIV infection remained off antiretroviral therapy significantly longer (P ‫؍‬ 0.03; log rank). Thus, our data suggest that the induction of HIV-specific CD4 T cell responses during acute HIV infection is beneficial overall and does not fuel disease progression. IMPORTANCECD4 T cells are critical for the clearance and control of viral infections. However, HIV preferentially infects HIV-specific CD4 T cells. Thus, their contribution to the control of HIV viremia is uncertain. Here, we study HIV-specific CD4 T cell responses from acute to chronic HIV infection and show that the generation of certain CD4 responses is associated with control rather than disease progression.

Antibody persistence and T-cell balance: Two key factors confronting HIV vaccine development

“…On one hand, they are intimately associated with protection through the provision of T-cell help for antibody production (34) and possibly direct cytolytic activity (9,25,(107)(108)(109). On the other hand, as predicted by Staprans et al (46) and confirmed elsewhere (97,98) in nonhuman primate studies, they can attenuate protection and lead to increased acquisition.…”

HIV-Infected Dendritic Cells Present Endogenous MHC Class II–Restricted Antigens to HIV-Specific CD4+ T Cells

“…The breadth and specificity of HS CD4 + T cell responses are associated with improved viral control and low viremia during acute and chronic infection, respectively (2,3). In particular, the generation of Gag-specific CD4 + T cells and their maintenance correlate with a better disease outcome and viral control, respectively (2,3).…”

HIV-1 Antibody Neutralization Breadth Is Associated with Enhanced HIV-Specific CD4 + T Cell Responses

“…To achieve this, we utilized an IFN-␥ secretion ELISPOT assay that we along with other investigators have used extensively to map T cell responses (13)(14)(15)(16). Using this assay, we were able to show increased HIVspecific CD4 ϩ T cell targeting in subjects with neutralizing breadth, but the caveats of this approach are that we were not able to delineate peripheral Tfh cells, and we were not able to investigate the functional characteristics of CD4 ϩ T cells that may be associated with optimal CD4 ϩ help to B cells.…”

“…Although HIV-specific CD4 ϩ T cell responses have been shown to be an important feature of viral immunity (10)(11)(12)(13)(14)(15)(16)(17)(18)(19), the specificity, function, and phenotypic characteristics of peripheral HIV-specific CD4…”