title: Severe immune dysregulation affects CD4⁺CD25(hi)FoxP3⁺ regulatory T cells in HIV-infected patients with low-level CD4 T-cell repopulation despite suppressive highly active antiretroviral therapy.
abstract: We hypothesized that CD4(+)CD25(hi)FoxP3(+) regulatory T cells (Tregs) could be involved in the high immune activation existing in patients with low-level CD4 T-cell repopulation under suppressive high active antiretroviral therapy (hereafter, "LLR patients"). Sixteen LLR patients, 18 human immunodeficiency virus (HIV)-infected controls (hereafter, "HIV controls"), and 16 healthy subjects were included. The frequency of CD4(+)CD25(hi)FoxP3(+) and HIV-specific Treg suppressive function were assessed. Relationships between Treg and CD4/CD8 activation (HLA-DR/CD38) and the frequency of naive CD4 T-cells were assessed. Low-level patients showed a higher Treg frequency but reduced HIV-specific immunosuppressive functions than HIV controls. Whereas in healthy subjects a strong negative correlation between Tregs and activated CD8 T cells emerged (r = -0.75, P < .001), it appeared disrupted in both HIV-infected groups (r = -0.06 and P = .83 for LLR patients; r = -0.11 and P = .68 for and HIV controls). Nevertheless, in LLR patients, Tregs negatively correlated with naive CD4 T cells (r = -0.60, P = .01), whereas there was no such correlation in HIV controls (r = -0.19, P = .46) or healthy subjects (r = -0.10, P = .73). Remarkably, a higher ratio of Tregs to naive CD4 T cells was observed in LLR patients than in HIV controls (P = .001) and healthy subjects (P < .001). We conclude that LLR patients have important alterations in immunoregulation involving CD4(+)CD25(hi)FoxP3(+) Tregs. In this scenario, the role of Tregs seems to be more related to the control of the naive CD4 T-cell homeostatic proliferation, rather than to the immune activation.
authors.affiliation: Immunovirology Laboratory, Institute of Biomedicine of Seville, Infectious Diseases Service and Department of Clinical Biochemistry, Virgen del Rocío University Hospital, IBIS/CSIC/University of Seville, Spain.
authors.forename: Gema
authors.initials: G
authors.lastname: Méndez-Lagares
authors.forename: María M
authors.initials: MM
authors.lastname: Pozo-Balado
authors.forename: María
authors.initials: M
authors.lastname: del Mar del Pozo Balado
authors.forename: Miguel
authors.initials: M
authors.lastname: Genebat
authors.forename: Miguel
authors.initials: M
authors.lastname: Genebat González
authors.forename: Antonio
authors.initials: A
authors.lastname: García Pergañeda
authors.forename: Antonio
authors.initials: A
authors.lastname: García Pergañeda Sánchez
authors.forename: Manuel
authors.initials: M
authors.lastname: Leal
authors.forename: Manuel
authors.initials: M
authors.lastname: Leal Noval
authors.forename: Yolanda María
authors.initials: YM
authors.lastname: Pacheco
authors.forename: Yolanda María
authors.initials: YM
authors.lastname: Pacheco López
mesh_terms: D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D015704:CD4 Antigens / Q000378:metabolism; D018791:CD4 Lymphocyte Count; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D060908:CTLA-4 Antigen / Q000378:metabolism; D016022:Case-Control Studies; D049109:Cell Proliferation / Q000187:drug effects; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D053450:Glucocorticoid-Induced TNFR-Related Protein / Q000378:metabolism; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D016130:Immunophenotyping; D007376:Interleukin-2 / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D012367:RNA, Viral / Q000097:blood; D013030:Spain; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism
chemical_list: D015704:CD4 Antigens; D060908:CTLA-4 Antigen; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D053450:Glucocorticoid-Induced TNFR-Related Protein; C508017:IL2RA protein, human; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D012367:RNA, Viral; C491405:TNFRSF18 protein, human