Despite the presence of HIV-specific responses, HIV reservoirs persist and pose obstacles for cure. Early pathogenic effects of HIV infection in secondary lymphoid tissues including the gut contribute to ineffective anti-viral immunity, which are not repaired by ART. MSC secrete immuno-modulatory molecules and have beneficial effects in clinical studies. Using the SIV model of AIDS, we tested the hypothesis that systemic MSC administration will modulate antigen presentation and enhance anti-viral immunity at mucosal sites and lead to better viral suppression and increased immune recovery.
Rhesus macaques with chronic SIV infection were administered with MSC by adoptive transfer and compared with SIV-infected and SIV-negative animals without MSC treatment. Virologic, immunologic, transcriptomic, metabolomic and microbiota (16s sequencing) analyses were performed. SIV RNA loads in plasma and tissue samples were determined by RTPCR and RNAscope. Changes in the T and B cell subset distribution and activation was measured by flow cytometry. SIV-specific cellular and humoral (SIV Env antibodies by ELISA) responses were measured and changes in the gene expression (RNAseq) were performed.
MSC-treated animals had decreased SIV viral loads that correlated with increased levels of activated B cells, SIV-specific CD8+ T cells and SIV Env-specific antibodies in peripheral blood compared to untreated controls. In the gut and lymph nodes, SIV RNA-positive cells were relocated to germinal centers and majority of them were PD1+. In contrast, SIV+ cells were dispersed in lamina propria. Transcriptomic analysis revealed enhanced immune networks supporting anti-viral immunity. Increased prevalence of Lactobacillus and enhanced Linoleic acid metabolism was detected.
Collectively, our data support the hypothesis that MSCs enhance the virus-specific cellular and humoral immune responses by corralling SIV+ cells to the lymphoid follicles and improving antigen presentation and activating immune cell networks. Thus, MSC can be used for reviving or tooling mucosal immunity in HIV infection for viral clearance.