Nagaraju Ruthu, Gowda Pruthvi S, Gunasekaran Durai M, Desai Anita S, Ranga Udaykumar, Masthi Ramesh N R, Venkataswamy Manjunatha M
Department of Neurovirology, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India.
Department of Community Medicine, Kempegowda Institute of Medical Sciences Hospital & Research Centre, Bengaluru, Karnataka, India.
mBio. 2025 May 14;16(5):e0057525. doi: 10.1128/mbio.00575-25. Epub 2025 Mar 25.
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 ( = -0.6769, < 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 ( = -0.6726, < 0.0001) or regulatory ( = -0.5627, < 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.
尽管采用了长期抑制性抗逆转录病毒疗法（ART），但由于CD4 + T细胞重建受损导致的免疫失调仍是降低HIV-1感染的免疫无应答者（INR，CD4 + T细胞≤350个/μL）发病率和死亡率的主要障碍。为了评估与CD4 + T细胞重建受损相关的潜在免疫因素，我们对HIV-1感染个体中CD4 + T细胞多个亚群进行了全面的免疫表型分析，这些个体的CD4 + T细胞水平高（> 350个/μL）和低（≤350个/μL），包括初治或接受ART治疗（中位数为10年）。与其他组相比，INR组中CXCR3 + CCR6 - Th1样循环滤泡辅助性T细胞（cTfh1）CD4 + T细胞的比例仅升高，与CD4 + T细胞呈负相关（r = -0.6769，P < 0.0001），表明与CD4 + T细胞恢复不完全密切相关。相比之下，与INR组相比，免疫应答者（IR，CD4 + T细胞> 350个/μL）中CXCR3 - CCR6 + Th17样cTfh细胞（cTfh17）比例较高，与CD4 + T细胞计数无相关性，表明与CD4 + T细胞恢复缺乏关联。此外，与IR组相比，INR组中活化的（CD4 + CD38 + HLA-DR +）和调节性的（CD4 + CD25 + / hi CD127 - / lo）CD4 + T细胞比例增加，这是之前已知的。在IR组和INR组中，还观察到CD4 + T细胞计数与活化的（r = -0.6726，P < 0.0001）或调节性的（r = -0.5627，P < 0.0001）CD4 + T细胞比例之间呈负相关。我们的研究强调，与cTfh细胞向CXCR3 + CCR6 - Th1样表型偏移相关的免疫失调可能是INR组中CD4 + T细胞恢复低效的主要原因，并且可作为CD4 + T细胞重建受损的标志。重要性免疫无应答者（INR）中CD4 + T细胞亚群比例的改变表明它们参与了CD4 + T细胞重建不良。逆转这些改变可能有助于防止CD4 + T细胞的损失。特别是，阻断cTfh细胞向CXCR3 + CCR6 - cTfh细胞亚群的极化可能有助于恢复INR组中的CD4 + T细胞计数，从而预防发病率和死亡率增加的风险。
