Altered differentiation is central to HIV-specific CD4⁺ T cell dysfunction in progressive disease

Dysfunction of virus-specific CD4⁺ T cells in chronic human infections is poorly understood. We performed genome-wide transcriptional analyses and functional assays of CD4⁺ T cells specific for human immunodeficiency virus (HIV) from HIV-infected people before and after initiation of antiretroviral therapy (ART). A follicular helper T cell (T_FH cell)-like profile characterized HIV-specific CD4⁺ T cells in viremic infection. HIV-specific CD4⁺ T cells from people spontaneously controlling the virus (elite controllers) robustly expressed genes associated with the T_H1, T_H17 and T_H22 subsets of helper T cells. Viral suppression by ART resulted in a distinct transcriptional landscape, with a reduction in the expression of genes associated with T_FH cells, but persistently low expression of genes associated with T_H1, T_H17 and T_H22 cells compared to the elite controller profile. Thus, altered differentiation is central to the impairment of HIV-specific CD4⁺ T cells and involves both gain of function and loss of function.