Immunological non-response in HIV-infected patients under effective ART is associated with increased circulating Th17 T helper cells

Background: Failure to normalize CD4+ T-cell count despite effective antiretroviral therapy (ART) is associated with increased T-cell activation and inflammation. Th17 T helper subpopulation (Th17) is characterized by the expression of the transcription factor RORgT and the secretion of pro-inflammatory cytokines, such as IL-17. Intestinal Th17 levels are severly impaired in HIV infection and not fully restored under ART. We evaluated the role of circulating Th17 levels in the immunological response to ART in HIV-infected patients. Materials and Methods: Cross-sectional study, single-site study. HIV-infected patients on ART for ≥24 months and plasma HIV-RNA<50 cp/mL for ≥12 months, matched for nadir CD4 T cell count were enrolled. Presence of opportunistic AIDS-related diseases, HBV or HCV coinfection, chronic inflammatory disorders, ongoing immunosuppressive therapy were exclusion criteria. Patients were classified as immunological responders (IRs) or non responders (INRs) if CD4 count was ≥500 or ≤350 cells/μL, respectively. HLADRII/CD4 circulating levels have been evaluated as marker of T-cell activation. Th17 circulating levels have been assessed by simultaneous expression of IL-17A and RORgT IL17A and RORgT were measured in unstimulated and in AT2-HIV-1 and LPS stimulated cells. Results. Thirty-nine HIV-infected patients (22 IRs; 17 INRs, 77% male, medians: age 47 years, time from HIV diagnosis 10 years, time with HIV-RNA<50cp/mL 57 months) were enrolled. INR patients were older (median 60 vs 43 years, p<0.001) and had a higher prevalence of past AIDS-defining illnesses (76% vs 18%, p<0.001). Current median CD4 count was 840 (IQR 718-1131) cells/μL in IRs vs 295 (IQR 256-343) cells/μL in INRs. HLADRII/CD4 levels (17.72.01% vs 9.73%, p=0.04) were significantly increased in unstimulated cell cultures of INRs. Significantly higher IL-17A and RORgT expression was seen in unstimulated CD4 of INRs as compared to IRs (– 0.46% vs. 0.20% p=0.046). AT-2 stimulation induced IL-17A and RORgTexpression in both IRs and INRs; however, IL-17 and RORgT expression was significantly increased in INRs compared to IRs (0.82% vs 0.32%, p=0.006). In the same way, LPS-stimulation induced IL-17A and RORgT expression in both IRs and INRs, resulting, however, in significantly increased expression of IL-17A and RORg in INRs as compared to IRs (0.71% vs 0.27%, p=0.015). At multivariate analysis, immunological response was independently associated with lower Th17 levels (mean change -0.42%, p=0.005) after adjustment for age and past AIDS event. Conclusions: Despite intestinal Th17 cells loss in HIV infection, incomplete CD4+ T cell response to ART in INRs is associated with increased circulating levels of Th17, possibly linked to a less efficient migration of this cellular subpopulation from blood to intestinal mucosa. The up-regulation of these pro-inflammatory mechanisms in INRs could contribute to the augmented incidence of HIV-related events and non-AIDS comorbidities.