Probiotics Reduce Inflammation in Antiretroviral Treated, HIV-Infected Individuals: Results of the "Probio-HIV" Clinical Trial

BACKGROUND: HIV infection results in damage to the gastrointestinal (GI) tract, microbial translocation and immune activation. These are not completely normalized with combined antiretroviral therapy (cART). Moreover, increate morbidity and mortality of cART-treated HIV-infected individuals is associated with inflammation. METHODS: In order to enhance GI tract immunity, we recruited and treated 20 HIV-infected humans with cART supplemented with probiotics and followed inflammation and immunological parameters (clinical trial number NCT02164344). 11 HIV seronegative subjects were included as control group. The enumeration of CD4+, CD8+, CD38+ and HLA-DR+ lymphocytes were evaluated on peripheral blood; HIV-RNA levels, sCD14, d-dimer, C-reactive protein (CRP) high sensitivity C-reactive protein (hsCRP), IL-6 and Lipopolysaccharide Binding Protein (LBP) were assayed on plasma. RESULTS: We observe that cART does not normalize the levels of immune activation in HIV positive patients anyway inflammation and markers of microbial translocation were significantly reduced with probiotic supplementation. Patients show a clear and statistically significant reduction in the levels of immune activation on CD4 T-lymphocytes, for both markers CD38 and HLA-DR and their simultaneous expression, LBP and hsCRP plasma levels after probiotic diet supplementation settling to values comparable to controls. CONCLUSIONS: Supplementing cART with probiotics in HIV-infected individuals may improve GI tract immunity and there by mitigate inflammatory sequelae, ultimately improving prognosis

IL-21 and Probiotic Therapy Improve TH17 Frequencies, Microbial Translocation, and Microbiome in ARV-Treated, SIV-Infected Macaques

Increased mortality in antiretroviral (ARV)-treated, HIV-infected individuals has been attributed to persistent immune dysfunction, in part due to abnormalities at the gastrointestinal barrier. In particular, the poor reconstitution of gastrointestinal T H 17 cells correlates with residual translocation of dysbiotic, immunostimulatory microflora across a compromised intestinal epithelial barrier. We have previously demonstrated that oral probiotics promote increased intestinal CD4+ T-cell reconstitution during ARV treatment in a non-human primate model of HIV infection; however, essential mucosal T-cell subsets, such as T H 17 cells, had limited recovery. Here, we sought to promote T H 17 cell recovery by administering IL-21 to a limited number of ARV-treated, probiotic-supplemented, SIV-infected pigtailed macaques. We demonstrate that probiotic and IL-21 supplementation of ARVs is associated with enhanced polyfunctional T H 17 expansion and reduced markers of microbial translocation and dysbiosis as compared to infected controls receiving ARVs alone. Importantly, treatment resulted in fewer morbidities compared to controls, and was independent of increased immune activation or loss of viral suppression. We propose that combining ARVs with therapeutics aimed at restoring intestinal stasis may significantly improve disease prognosis of ARV-treated, HIV-infected, individuals

Effects of probiotics on T-cells activation in patients with CD4 count less than 250 cells/μl.

<p>Longitudinal assessment of CD38 and HLA-DR markers and their simultaneous expression on CD4 T cells in peripheral blood. in patients with a CD4 count less than 250 cells/μl at HIV infection diagnosis. P values <0.05 were considered statistically significant.</p

Demographic, immunological and virological characteristics of the 20 HIV-infected patients and 11 controls included in the study.

<p>Demographic, immunological and virological characteristics of the 20 HIV-infected patients and 11 controls included in the study.</p

IL-6, nadir and immune activation at baseline.

<p>IL-6 levels at T0 were inversely correlated to CD4-Nadir (A) and CD4% (B), and positively correlated with the frequencies of activated, CD4+CD38+ T-cells (C). P values <0.05 were considered statistically significant; r represents correlation coefficient.</p

The CONSORT flow diagram of the clinical trial.

<p>Experimental design of the study.</p

Levels of immune activation according to the age on CD4+ T-cells.

<p>Extent of expression and co-expression of activation markers CD38 and HLA-DR on CD4+ T-lymphocytes before (T0) and after probiotics’ intake (T1) in patients with less (A) and more (B) than 55 years. Horizontal bars in the scatter plot represent mean value with SD. P values <0.05 were considered statistically significant.</p

HsCRP plasma levels.

<p>High-sensitivity C-reactive protein (hsCRP) distribution in patients before (T0), and after probiotics’ assumption (T1) compared with controls Horizontal bars in the scatter plot represent mean value with SD. P values <0.05 were considered statistically significant.</p