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

Abstract

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 cTfh exhibited a predominant Th1-like phenotype and function when compared to cTfh of other specificities, contrasting with a reduction in Th1-functions in HIV-specific non-cTfh. Using longitudinal samples, we demonstrate that this distinct HIV-specific cTfh 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.

Immunogenic profile of SARS-CoV-2 spike in individuals recovered from COVID-19

“…Expansion of cTFH1 is well characterized following seasonal influenza immunisation, where peak frequencies in the blood correlate with both plasmablast expansion and subsequent serum neutralising antibody titres 23,30,35 . Similarly, bias toward CXCR3 + phenotypes is reported for antigen-specific cTFH in many chronic infections 36,37 . The functional significance of CXCR3 + cTFH during SARS-CoV-2 infection is currently unclear, however may reflect differences in lymph node TFH activity or egress from the GC.…”

Single-cell immune profiling reveals the impact of antiretroviral therapy on HIV-1-induced immune dysfunction, T cell clonal expansion, and HIV-1 persistencein vivo

“…11). As previously reported, KLRB1 (CD161) cells 64 , Th1 cells 25 , Th17 cells 65 , CXCR5 + cells 65,66 , and naïve cells 29 may harbor HIV-1-infected cells, although we found that naïve cells were significantly dis-enriched for HIV-1 RNA + cells ( Supplementary Fig. 11a).…”

TFH Cells Induced by Vaccination and Following SIV Challenge Support Env-Specific Humoral Immunity in the Rectal-Genital Tract and Circulation of Female Rhesus Macaques

“…While increased cytokine release by T FH cells has been linked to IgA responses in mice ( 106 ), SIV replication has been suggested to promote accumulation of activated IL-21 producing T FH cells with skewed B cell maturation in rhesus macaques ( 107 ). Other studies have shown that SIV infection in rhesus macaques and HIV infection in humans provokes Th1 polarization of T FH cells ( 43 , 108 ) while Th1 skewed T FH cells were shown to enhance the magnitude of anti-SIV IgA responses ( 109 ). It is possible that SIV infection may have determined functional and phenotypic changes of cT FH cells in blood which could have contributed to IgA-skewed release by peripheral B cells.…”