Higher proportions of circulating CXCR3+ CCR6− Tfh cells as a hallmark of impaired CD4+ T-cell recovery in HIV-1-infected immunological non-responders

Despite long-term suppressive antiretroviral therapy (ART), immune dysregulation due to impaired reconstitution of CD4+ T cells is a major hurdle for reducing morbidity and mortality in HIV-1-infected immunological non-responders (INRs, CD4+ T cells ≤350 cells/µL). To evaluate potential immunological factors associated with impaired CD4+ T-cell reconstitution, we performed comprehensive immunophenotyping of multiple subsets of CD4+ T cells among HIV-1-infected individuals with high (>350 cells/µL) and low (≤350 cells/µL) CD4+ T cells, either ART-naïve or ART-exposed (median, 10 years). In comparison to other groups, INRs showed exclusively elevated proportions of CXCR3+ CCR6- Th1-like circulatory T follicular helper (cTfh1) CD4+ T cells, correlating negatively with CD4+ T cells (<i>r</i> = -0.6769, <i>P</i> < 0.0001), suggesting a strong association with incomplete CD4+ T-cell recovery. In contrast, compared to INRs, higher proportions of CXCR3- CCR6+ Th17-like cTfh cells (cTfh17) in immunological responders (IRs, CD4+ T cells >350 cells/µL) showed no correlation with CD4+ T-cell counts, suggesting a lack of association with CD4+ T-cell recovery. Additionally, proportions of activated (CD4+ CD38+ HLA-DR+) and regulatory (CD4+ CD25+/hi CD127-/lo) CD4+ T cells were increased in INRs compared to IRs, as previously known. A negative correlation was also observed between the CD4+ T-cell counts and activated (<i>r</i> = -0.6726, <i>P</i> < 0.0001) or regulatory (<i>r</i> = -0.5627, <i>P</i> < 0.0001) CD4+ T-cell proportions among IRs and INRs. Our study highlights that immune dysregulation associated with skewing of cTfh cells toward CXCR3+ CCR6- Th1-like phenotype may be the leading cause of inefficient CD4+ T-cell recovery in INRs and can serve as a hallmark of impaired CD4+ T-cell reconstitution.IMPORTANCEThe altered proportions of CD4+ T-cell subsets in immunological non-responders (INRs) indicate their involvement in poor CD4+ T-cell reconstitution. Reversing these alterations may help prevent the loss of CD4+ T cells. Particularly, blocking cTfh-cell polarization toward CXCR3+ CCR6- cTfh-cell subset may help restore CD4+ T-cell counts in INRs, thereby preventing increased risk of morbidity and mortality.