Higher proportions of circulating CXCR3+ CCR6− Tfh cells as a hallmark of impaired CD4+ T-cell recovery in HIV-1-infected immunological non-responders
ABSTRACT 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 imm...
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American Society for Microbiology
2025-05-01
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| Online Access: | https://journals.asm.org/doi/10.1128/mbio.00575-25 |
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| author | Ruthu Nagaraju Pruthvi S. Gowda Durai M. Gunasekaran Anita S. Desai Udaykumar Ranga Ramesh N. R. Masthi Manjunatha M. Venkataswamy |
| author_facet | Ruthu Nagaraju Pruthvi S. Gowda Durai M. Gunasekaran Anita S. Desai Udaykumar Ranga Ramesh N. R. Masthi Manjunatha M. Venkataswamy |
| author_sort | Ruthu Nagaraju |
| collection | DOAJ |
| description | ABSTRACT 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 (r = −0.6769, P < 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 (r = −0.6726, P < 0.0001) or regulatory (r = −0.5627, P < 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. |
| format | Article |
| id | doaj-art-ce38998ffaa14cd8a26de059eba82e0e |
| institution | DOAJ |
| issn | 2150-7511 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | American Society for Microbiology |
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| series | mBio |
| spelling | doaj-art-ce38998ffaa14cd8a26de059eba82e0e2025-08-20T02:59:04ZengAmerican Society for MicrobiologymBio2150-75112025-05-0116510.1128/mbio.00575-25Higher proportions of circulating CXCR3+ CCR6− Tfh cells as a hallmark of impaired CD4+ T-cell recovery in HIV-1-infected immunological non-respondersRuthu Nagaraju0Pruthvi S. Gowda1Durai M. Gunasekaran2Anita S. Desai3Udaykumar Ranga4Ramesh N. R. Masthi5Manjunatha M. Venkataswamy6Department of Neurovirology, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, IndiaDepartment of Community Medicine, Kempegowda Institute of Medical Sciences Hospital & Research Centre, Bengaluru, Karnataka, IndiaDepartment of Biostatistics, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, IndiaDepartment of Neurovirology, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, IndiaJawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru, Karnataka, IndiaDepartment of Community Medicine, Kempegowda Institute of Medical Sciences Hospital & Research Centre, Bengaluru, Karnataka, IndiaDepartment of Neurovirology, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, IndiaABSTRACT 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 (r = −0.6769, P < 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 (r = −0.6726, P < 0.0001) or regulatory (r = −0.5627, P < 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.https://journals.asm.org/doi/10.1128/mbio.00575-25HIV-1immunological non-respondersaltered CD4+ T-cell subsetsimpaired immunological reconstitutioncirculatory T follicular helper cellscTfh |
| spellingShingle | Ruthu Nagaraju Pruthvi S. Gowda Durai M. Gunasekaran Anita S. Desai Udaykumar Ranga Ramesh N. R. Masthi Manjunatha M. Venkataswamy Higher proportions of circulating CXCR3+ CCR6− Tfh cells as a hallmark of impaired CD4+ T-cell recovery in HIV-1-infected immunological non-responders mBio HIV-1 immunological non-responders altered CD4+ T-cell subsets impaired immunological reconstitution circulatory T follicular helper cells cTfh |
| title | Higher proportions of circulating CXCR3+ CCR6− Tfh cells as a hallmark of impaired CD4+ T-cell recovery in HIV-1-infected immunological non-responders |
| title_full | Higher proportions of circulating CXCR3+ CCR6− Tfh cells as a hallmark of impaired CD4+ T-cell recovery in HIV-1-infected immunological non-responders |
| title_fullStr | Higher proportions of circulating CXCR3+ CCR6− Tfh cells as a hallmark of impaired CD4+ T-cell recovery in HIV-1-infected immunological non-responders |
| title_full_unstemmed | Higher proportions of circulating CXCR3+ CCR6− Tfh cells as a hallmark of impaired CD4+ T-cell recovery in HIV-1-infected immunological non-responders |
| title_short | Higher proportions of circulating CXCR3+ CCR6− Tfh cells as a hallmark of impaired CD4+ T-cell recovery in HIV-1-infected immunological non-responders |
| title_sort | higher proportions of circulating cxcr3 ccr6 tfh cells as a hallmark of impaired cd4 t cell recovery in hiv 1 infected immunological non responders |
| topic | HIV-1 immunological non-responders altered CD4+ T-cell subsets impaired immunological reconstitution circulatory T follicular helper cells cTfh |
| url | https://journals.asm.org/doi/10.1128/mbio.00575-25 |
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