Regulatory T-Cell Activity But Not Conventional HIV-Specific T-Cell Responses Are Associated With Protection From HIV-1 Infection

Abstract

Objective: Two distinct hypotheses have been proposed for T-cell involvement in protection from HIV-1 acquisition. First, HIV-1-specific memory T-cell responses generated on HIV-1 exposure could mount an efficient response to HIV-1 and inhibit the establishment of an infection. Second, a lower level of immune activation could reduce the numbers of activated, HIV-1-susceptible CD4 T cells, thereby diminishing the likelihood of infection.

Methods: To test these hypotheses, we conducted a prospective study among high-risk heterosexual men and women, and tested peripheral blood samples from individuals who subsequently acquired HIV-1 during follow-up (cases) and from a subset of those who remained HIV-1 uninfected (controls).

Results: We found no difference in HIV-1-specific immune responses between cases and controls, but Treg frequency was higher in controls as compared with cases and was negatively associated with frequency of effector memory CD4 T cells.

Conclusions: Our findings support the hypothesis that low immune activation assists in protection from HIV-1 infection.

Conflict of interest statement

Conflicts of Interest: The authors declare no conflict of interests.

Figures

Figure 1. HIV-1-specific T-cell responses are comparable in cases and controls

Magnitude of HIV-specific CD4+ T-cell responses as measured by percentage of cells secreting IFN-γ and TNF-α following stimulation with HIV-1 peptide pools (top). Magnitude of HIV-specific CD8+ T-cell responses as measured by percentage of cells secreting IFN-γ and localization of CD107a on the cell membrane following stimulation with HIV peptide pools (bottom).

Figure 2. Regulatory T cell (Treg) frequency is higher in controls compared to cases

A) Gating scheme used to quantify the frequencies of Tregs as fractions of CD3+ or CD3+ CD4+ T cells. B) Examples of plots obtained in samples with high (top) and low (bottom) Treg frequency. C) Boxplot showing the distribution of Treg frequency as percentage of CD3+ T-cells (left) and of CD4+ T-cells (right) for controls (black bars) and cases (grey bars). D) Boxplot displaying frequency of Tregs expressing the activation markers CD39, CTLA-4 and ICOS for controls (black bars) and cases (grey bars).

Figure 3. Treg frequency correlates negatively with T cell activation and positively with the frequency of central memory (TCM) CD4+ T cells

Correlation plot and linear regression lines showing the associations between Treg frequency and T-cell activation frequency (top); Treg and TCM frequencies (center) Treg and TEM frequencies (bottom). Data for CD4+ T-cells are shown on the left part of the figure and CD8+ T-cells on the right.

Figure 4. Treg frequency negatively correlates with HIV-specific CD4+, but not CD8+ T-cell responses

Correlation plot and linear regression lines showing the associations between Treg frequency and magnitude of HIV-specific responses to Env (top plot), Gag (central plot) and Tat (bottom plot) mediated by CD4+ (left) and CD8+ (right) T-cells.