UC Davis

Mesenchymal stem cells (MSCs) are stromal stem cells that can maintain tissue homeostasis, modulate inflammatory responses, and potentially enhance tissue repair. Given their immunomodulatory functions, these cells could play a role in the repair of the virally inflamed and functionally damaged gut. Human immunodeficiency virus (HIV) caused severe CD4+ T-cell depletion and epithelial barrier disruption and impaired mucosal immunity. Using the simian immunodeficiency virus (SIV) model of HIV/AIDS, MSC treatment was previously shown to inhibit SIV replication, restore CD4+ T-cell levels and CD8+ T-cell levels in the periphery and the gut, and enhance B-cell and antibody responses in the gut of SIV-infected rhesus macaques. However, the beneficial effects of MSC in the context of antiretroviral therapy (ART) are not well investigated. We propose that MSC can reverse SIV/HIV-induced gut mucosal damage, reduce SIV/HIV loads, and enhance antiviral immune defenses in HIV and SIV infections during ART. In this longitudinal study, the effects of MSC therapy in SIV-infected and ART-treated rhesus macaques were studied to investigate whether MSC treatment leads to an additional decrease in SIV loads, enhanced antiviral immunity, and rapid immune recovery and reconstitution during ART. Over the course of the study, a group of SIV-infected and ART-treated rhesus macaques was given three intravenous infusions of bone-marrow-derived rhesus macaque MSCs, and another SIV-infected and ART-treated rhesus macaque group was given saline as a form of negative control. The SIV loads and the levels of T-cell subpopulations from peripheral blood mononuclear cells (PBMCs) and lamina propria lymphocytes (LPLs) were measured via qRT-PCR and flow cytometry, respectively, to understand how MSC treatment affects SIV loads and specific T-cell subpopulation levels, especially the peripheral and gut CD4+ T-cells levels, during SIV infection and ART. Based on the results of the study, the ART resulted in profound suppression of viral replication and decreased viral loads. MSC treatment did not cause any further decrease in plasma SIV loads during ART. However, MSC treatment resulted in higher CD4+ T-cell levels in the peripheral blood of SIV-infected animals receiving ART. Initial evaluation of the gut CD4+ T-cell levels during early time points did not show significant changes due to MS treatment. Our data show that MSC treatment had a positive effect on increasing CD4+ T-cell levels in the peripheral blood during ART, suggesting that MSC had a beneficial effect on the restoration of T-cell numbers and immunity in addition to the immune restoration due to the ART-mediated viral suppression. These findings highlight the need of investigating the long-term effects of MSC treatment on CD4+ T-cell restoration and antiviral immunity.