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 prior and after initiation of antiretroviral therapy (ART). A follicular helper T cell (T(FH) cell)–like profile characterized HIV-specific CD4(+) T cells in viraemic infection. HIV-specific CD4(+) T cells from people spontaneously controlling the virus (elite controllers) robustly expressed genes associated with the T(H)1, T(H)17 and T(H)22 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(H)1, T(H)17 and T(H)22 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.