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.
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