Probiotics to HIV-Infected Immunological Nonresponders: Altered Mucosal Immunity and Microbial Diversity Restricted to Ileum.

BACKGROUND: HIV-infected immunological nonresponders (INRs) have increased risk of non-AIDS morbidity and compromised gut barrier immunity. Probiotics are widely used to improve health. We assessed the effects of probiotics in INRs with a comprehensive analysis of gut immunity and microbiome in terminal ileum and sigmoid colon. METHODS: The study involved clinical intervention with five-strain probiotic capsules (1.2 × 1010 CFUs/d) for 8 weeks in 20 INRs with CD4+ T-cell counts <400 cells/µL and plasma HIV RNA <50 copies/mL for more than 3.5 years. Colonoscopy with sampling of gut biopsies from terminal ileum and sigmoid colon and fecal and blood sampling were performed before and after the intervention. Flow cytometry (cytokine production, immune activation, and exhaustion), ELISA (inflammation, microbial translocation, and enterocyte damage), and 16S rRNA sequencing analyses were applied. RESULTS: In the terminal ileum, increased alpha diversity, increased abundance of Bifidobacterium sp., and decreased frequencies of IL-22+ CD4+ T cells were observed. The increased abundance of Bifidobacterium sp. in the terminal ileum correlated with increased fraction of CD4+ T cells in the same compartment (r = 0.54, P = 0.05) and increased CD4/CD8 ratio in peripheral blood (r = 0.49, P = 0.05). There were no corresponding changes in the sigmoid colon and no changes in fecal microbiome. Probiotic intervention did not affect peripheral blood CD4 count, viral load, or soluble markers of inflammation and microbial translocation. CONCLUSIONS: Probiotics induced segment-specific changes in the terminal ileum but did not affect systemic CD4 counts in INRs. Further clinical studies are warranted to recommend probiotics to INRs.

Activated dendritic cells and monocytes in HIV immunological nonresponders: HIV-induced interferon-inducible protein-10 correlates with low future CD4+ recovery.

OBJECTIVE: To explore monocyte and dendritic cell immune responses, and their association with future CD4 gain in treated HIV patients with suboptimal CD4 recovery. DESIGN: A cross-sectional study of HIV-infected, virally suppressed individuals on antiretroviral therapy for at least 24 months; 41 immunological nonresponders (INRs) (CD4 cell count <400 cells/µl) and 26 immunological responders (CD4 cell count >600 cells/µl). Ten HIV-infected antiretroviral therapy-naive and 10 HIV-negative healthy persons served as controls. CD4 cell counts were registered after median 2.4 and 4.7 years. METHODS: Monocyte, dendritic-cell and T-cell activation and regulatory T cells (Tregs) were analyzed by flow cytometry. In INR and immunological responder subgroups matched on age and nadir CD4 cell count, upregulation of interferon-inducible protein-10 (IP-10) and indoleamine 2,3-dioxygenase in monocytes and dendritic cells and cytokines in cell supernatants were measured in vitro in peripheral blood mononuclear cells stimulated with aldrithiol-2-inactivated HIV-1. RESULTS: The INR group displayed higher spontaneous activation of both monocytes (HLA-DR) and myeloid and plasmacytoid dendritic cells (HLA-DR, CD83 and CD86) compared with immunological responders, and this was associated with increased T-cell activation (CD38HLA-DR), an effector memory T-cell phenotype and activated Tregs. The IP-10 response in monocytes after in-vitro HIV stimulation was negatively associated with prospective CD4 gain. IP-10, indoleamine 2,3-dioxygenase and cytokines levels were comparable between the groups, but inversely correlated with activated Tregs in INRs. CONCLUSION: HIV-infected individuals with suboptimal immune recovery demonstrated more activated monocytes and in particular dendritic cells, compared with patients with acceptable CD4 gain. A high level of HIV-specific IP-10 expression in monocytes may be predictive of future CD4 recovery.