Gut germinal center regeneration and enhanced antiviral immunity by mesenchymal stem/stromal cells in SIV infection

Abstract

While antiretroviral therapy suppresses HIV replication, it does not eliminate viral reservoirs or restore damaged lymphoid tissue, posing obstacles to HIV eradication. Using the simian immunodeficiency virus (SIV) model of AIDS, we investigated the effect of mesenchymal stem/stromal cell (MSC) infusions on gut mucosal recovery, anti-viral immunity, viral suppression and determined associated molecular/metabolic signatures. MSC administration to SIV-infected macaques resulted in viral reduction and heightened virus-specific responses. Marked clearance of SIV-positive cells from gut mucosal effector sites was correlated with robust regeneration of germinal centers (GC), restoration of follicular B cells, T follicular helper (Tfh) cells, and enhanced antigen presentation by viral trapping within follicular dendritic cell network. Gut transcriptomic analyses showed increased antiviral response mediated by unique pathways of type-I/II IFN signaling, viral restriction factors, innate immunity and B cell proliferation and provided the molecular signature underlying enhanced host immunity. Metabolic analysis revealed strong correlations between B and Tfh cell activation, anti-SIV antibodies, and IL-7 expression with enriched retinol metabolism, which facilitates gut homing of antigen-activated lymphocytes. Our findings discover new MSC functions in modulating anti-viral immunity for enhanced viral clearance predominantly through type-I/II IFN signaling and B cell signature and provide a roadmap for multi-pronged HIV eradication strategies.

Altered Expression of ACE2 and Co-receptors of SARS-CoV-2 in the Gut Mucosa of the SIV Model of HIV/AIDS

“…RNAseq analysis was performed in Illumina HiSeq 4,000 system as previously described ( Weber et al, 2021 ). In brief, total RNA was extracted using the (QIAGEN RNeasy RNA isolation kit) from ileum tissues and treated with DNase (QIAGEN RNase-Free DNase Kit).…”

Mesenchymal Stem Cells and MSCs-Derived Extracellular Vesicles in Infectious Diseases: From Basic Research to Clinical Practice

“…One of the most interesting studies focused on the use of MSCs to increase antiviral immune activity and minimize the amount of virus. It has been shown that the administration of MSCs, even in the absence of antiviral drugs, can enhance the host’s antiviral response due to the restoration of lymphoid follicles and mucosal immunity, all of which become the target of the virus at an early stage [ 194 ]. The results of scientific and clinical studies provide an appropriate scientific basis for the future use of MSCs in the treatment of HIV and other infectious diseases.…”

Mesenchymal stem cells-based therapy in liver diseases

“…However, MSCs can promote the proliferation of virus-specific immune cells and their antiviral exertion [ 20 , 21 ]. For example, using the SIV model of AIDS, some researchers have recently found that MSCs can restore antiviral immunity by reconstituting damaged lymphoid follicles, as evidenced by robust regeneration of germinal centers, as well as restoration of follicular B cells and Tfh cells leading to increased levels of anti-SIV antibodies and SIV-specific CD8 + T cells, resulting in viral reduction [ 539 ]. Similarly, a phase II randomized, double-blinded, multicenter, placebo- controlled, dose-determination trial in 72 immune nonresponder (INR) patients with chronic HIV-1 infection showed that treatment with huMSCs was safe, with a significant increase in CD4 + T cells counts in HIV-infected patients after 48 weeks of treatment, although a larger cohort studies are needed to further confirm the immune reconstitution efficacy of MSCs [ 540 ].…”