Altered T-Cell Subsets are Associated with Dysregulated Cytokine Secretion of CD4⁺ T Cells During HIV Infection

CD4⁺ T cells play a critical role in the regulation of immunopathogenesis in HIV infection. Previous studies have shown contradictory results of the CD4⁺ T-cell responses in people living with HIV (PLHIV).

A cross-sectional study was performed on 40 healthy controls, 134 ART-naïve PLHIV, and 34 individuals who experienced 3-year ART with low baseline CD4 count from 4 August 2016 to 23 January 2019. We determined the frequencies of CD4⁺ T-cell subsets and described the cytokine secretion pattern of total and subsets of CD4⁺ T cells in these individuals.

We found that CD4⁺ T cells in PLHIV displayed enhanced secretion of pro-inflammation cytokines and polyfunctionality due to HIV disease progression (r = -0.282, P = 0.0035 for IFN-γ; r = -0.412, P = 0.0002 for TNF-α; r = -0.243, P < 0.0001 for GM-CSF; r = -0.252, P = 0.0093 for IFN-γ⁺ TNF-α⁺ cells). However, the altered T-cell subsets, as presented by the loss of naïve cells and expansion of memory/effector population in PLHIV, were associated with discordant results in total and subsets of CD4⁺ T cells. As major cytokine-producing T subsets, effector/memory CD4 subsets showed impaired cytokine production (P < 0.05). We further demonstrated that 3-year ART treatment could improve CD4 counts by increasing the pool of naïve T cells but could not restore cytokine secretion in CD4⁺ T-cell subsets (P < 0.05).

These data identified the impaired capacity of cytokine secretion in CD4⁺ T-cell subsets due to HIV disease progression, and the altered T-cell subsets were associated with pseudo-elevation of cytokine production in total CD4⁺ T cells. This study collectively suggested the importance of therapies that can preserve and/or enhance the function of CD4⁺ T cells in strategies of HIV remission.