Persistent expansion and Th1-like skewing of HIV-specific circulating T follicular helper cells during antiretroviral therapy

Background: Untreated HIV infection leads to alterations in HIV-specific CD4(+) T cells including increased expression of co-inhibitory receptors (IRs) and skewing toward a T follicular helper cell (Tfh) signature. However, which changes are maintained after suppression of viral replication with antiretroviral therapy (ART) is poorly known. Methods: We analyzed blood CD4(+) T cells specific to HIV and comparative viral antigens in ART-treated people using a cytokine-independent activation-induced marker assay alone or in combination with functional readouts. Findings: In intra-individual comparisons, HIV-specific CD4(+) T cells were characterized by a larger fraction of circulating Tfh (cTfh) cells than CMV- and HBV-specific cells and preferentially expressed multiple IRs and showed elevated production of the Tfh cytokines CXCL13 and IL-21. In addition, HIV-specific cTth exhibited a predominant Th1-like phenotype and function when compared to cTth of other specificities, contrasting with a reduction in Th1-functions in HIV-specific non-cTth. Using longitudinal samples, we demonstrate that this distinct HIV-specific cTth profile was induced during chronic untreated HIV infection, persisted on ART and correlated with the translation-competent HIV reservoir but not with the total HIV DNA reservoir. Interpretation: Expansion and altered features of HIV-specific cTfh cells are maintained during ART and may be driven by persistent HIV antigen expression. (C) 2020 The Author(s). Published by Elsevier B.V.