(O4) Gut mucosal CD4 T cells of immunological non-responders with low CD4/CD8 ratio have increased cytokine production, which may be reduced by probiotics
Malin H Meyer-Myklestad(1,3), Asle W Medhus(2), Birgitte Stiksrud(1,3), Dag Kvale(1,3), Anne Ma D Riise(1,3), Dag Henrik Reikvam(1)
(1) Department of infectious diseases, Oslo University Hospital Ullevål, Norway. (2) Department of Gastroenterology, Oslo University Hospital, Ullevål, Norway. (3) Institute of Clinical Medicine, Department of Infectious Diseases, University of Oslo, Norway.
Background: HIV infection causes a depletion of CD4 T cells in the gut mucosa and is associated with increased inflammation and immune activation. Impaired gut mucosal barrier function may contribute to increased non-AIDS morbidity, especially in the immunological non-responders (INR), who are characterized by an insufficient CD4 recovery in spite of virologic response to ART. However, the contribution of lamina propria T cells to a dysfunctional mucosa remains to be determined. Probiotics may improve gut mucosal immune function in HIV infection.
Methods: In a cross-sectional study we included 20 INRs (def.: ART treated > 4 years with HIV RNA <50 copies/ml and CD4 count 3,5 years) and 20 immunological responders (IR) (def.: ART treated > 4 years with HIV RNA 600 cells/µL for >3,5 years) matched on sex, age and nadir CD4 count. All participants underwent colonoscopy where mucosal biopsies from the terminal ileum and the sigmoid colon were collected. In a subsequent phase II exploratory interventional trial (NCT02640625), the INRs received probiotics (>1,2*1010 cfu/day with five mixed probiotic strains) for 8 weeks and were re-examined by colonoscopy. Lamina propria mononuclear cells were isolated from the mucosal biopsies, stimulated with PMA/ionomycin and IL-17, IL-22 and IFNγ expressions were measured by flowcytometry.
Results: Per protocol comparisons of mucosal CD4 T cell production of individual cytokines did not reveal significant differences between INRs and IRs. After stratifying both INRs and IRs according to blood CD4/CD8 T cell ratio by either low (def.: 1.0, n=10), two-way ANOVA analysis demonstrated that INRs with low CD4/CD8-ratio had significantly higher fractions of IL-22, IL-17 and IFNγ positive CD4 T cells than IRs with high CD4/CD8 T cell ratio (p=0.049). The probiotic supplement was generally well tolerated. 19/20 of the study subjects completed the interventional study. Probiotics significantly reduced mucosal CD4 T cell IL-22 production in terminal ileum (p=0.036), but did not affect capacity for IL-17 or IFNγ production.
Conclusions: Mucosal CD4 T cells from HIV infected people with unfavorable CD4/CD8 T cell ratio have increased capacity for production of key mucosal cytokines. This capacity may be reduced by probiotics.