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 Gag-specific 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.

Importance: CD4 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.

FIG 1

HIV-specific CD4 T cell responses showed similar frequencies and immunodominance profiles in acute and chronic infection. HIV-specific CD4 responses from different time points postpresentation were screened against a panel of OLPs spanning HIV's proteome of Gag, Nef, and gp120. HIV-specific CD4 T cell responses obtained from a chronically infected cohort, as published previously (13), are shown in comparison (bottom). The y axes show the frequencies of epitope-specific CD4 T cell responses to the respective OLPs. The HIV proteins corresponding to the OLP positions are shown on the x axes. Particular OLPs of interest are shown above the corresponding values.

FIG 2

HIV-specific CD4 T cell responses remain stable within the first year of infection. (A) Breadth of HIV-specific CD4 T cell responses for 55 subjects shown at baseline and 2, 4, 6, and 12 months postpresentation. We found a nonsignificant decrease in breadth from acute infection (average, 5.5) to 12 months postinfection (average, 3.3). The open circles represent individuals identified during Fiebig stages 2, 3, and 4; the gray circles represent individuals identified during Fiebig stages 5 and 6. (B) Matched-pair analysis of the breadths of HIV-specific CD4 T cell responses in 12 individuals at baseline and 12 months postinfection showed divergent results: decrease of breadth in 6/12, increase of breadth 5/12, and no change in breadth in 1/12. (C) Cross-sectional analysis of the total magnitudes of HIV-specific CD4 T cell responses for 55 subjects at baseline and 2, 4, 6, and 12 months postpresentation. We found an overall tendency of decrease in magnitude from acute (baseline, 1,333 ± 1,721 [SD] SFC/M) to chronic (12 months postpresentation, 703.9 ± 877.5 SFC/M) infection that was not significant. (D) Matched-pair analysis of the magnitude of HIV-specific CD4 T cell responses in 12 individuals at baseline and 12 months postpresentation showed an overall tendency of a decrease of magnitude that was not statistically significant.

FIG 3

Stable dominance pattern of Gag-specific CD4 T cell responses over time. (A) Overall magnitudes (in SFC/M) of HIV-specific CD4 T cell responses for Gag, Nef, and gp120 at 0 and 12 months after diagnosis of acute HIV infection. While there was a nonsignificant decrease in magnitude in responses against Gag and gp120, the responses against Nef remained stable. The error bars indicate standard errors of the mean (SEM). (B) Breadth of HIV-specific CD4 T cell responses for Gag, Nef, and gp120 at 0 and 12 months after diagnosis of acute HIV infection. Against Gag and gp120, the breadth of responses decreased nonsignificantly, while the responses against Nef remained stable. The error bars indicate SEM. (C) Contributions to total HIV-specific CD4 T cell responses for Gag, Nef, and gp120 at 0 and 12 months after diagnosis of acute HIV infection. Gag had the highest percentage of HIV-specific CD4 T cell responses, followed by gp120 and Nef. While the responses against Gag and Nef remained stable, the responses against gp120 showed a nonsignificant decrease in the contribution to the total HIV-specific CD4 T cell responses from acute to chronic infection. The error bars indicate SEM. (D) Magnitudes (in SFC/M) of HIV-specific CD4 T cell responses against selected overlapping peptides for four subjects at different stages of infection from 0 to 12 months postpresentation where data were available. A prevalent pattern is the initial expansion of responses against specific peptides, followed by contraction. While some of the responses were present at all stages of infection, several fully contracted or appeared only during chronic infection.

FIG 4

Association of Gag-specific CD4 T cell responses and clinical outcome. (A) The contribution of Gag-specific CD4 T cell responses as a percentage of the total HIV-specific CD4 T cell response was significantly inversely correlated with a low viral set point (R = −0.5; P = 0.03; Spearman rank test). (B) The contribution of Env-specific CD4 T cell responses tended to be associated with a higher viral set point (R = 0.4; P = 0.06; Spearman rank test). (C) A low Env/Gag ratio was significantly associated with a low viral set point (R = 0.49; P = 0.03; Spearman rank test). (D) Survival analysis of the time patients remained off antiretroviral therapy. Individuals with higher Env-specific (n = 7) than Gag-specific (n = 12) CD4 T cell responses at baseline initiated HAART significantly earlier than individuals with higher Gag-specific than Env-specific CD4 T cell responses (median time to HAART, 275 days, versus median time to HAART, 596 days, respectively; P = 0.03; log rank test).