Gut germinal center regeneration and enhanced antiviral immunity by mesenchymal stem/stromal cells in SIV infection
Mariana G. Weber, Chara J. Walters-Laird, Amir Kol, Clarissa Santos Rocha, Lauren A. Hirao, Abigail Mende, Bipin Balan, Juan Arredondo, Sonny R. Elizaldi, Smita S. Iyer, Alice F. Tarantal, Satya Dandekar
Mariana G. Weber, Chara J. Walters-Laird, Amir Kol, Clarissa Santos Rocha, Lauren A. Hirao, Abigail Mende, Bipin Balan, Juan Arredondo, Sonny R. Elizaldi, Smita S. Iyer, Alice F. Tarantal, Satya Dandekar
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Research Article AIDS/HIV

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

Abstract

Although antiretroviral therapy suppresses HIV replication, it does not eliminate viral reservoirs or restore damaged lymphoid tissue, posing obstacles to HIV eradication. Using the SIV model of AIDS, we investigated the effect of mesenchymal stem/stromal cell (MSC) infusions on gut mucosal recovery, antiviral immunity, and 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, restoration of follicular B cells and T follicular helper (Tfh) cells, and enhanced antigen presentation by viral trapping within the follicular DC network. Gut transcriptomic analyses showed increased antiviral response mediated by 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. We identified potentially new MSC functions in modulating antiviral immunity for enhanced viral clearance predominantly through type I/II IFN signaling and B cell signature, providing a road map for multipronged HIV eradication strategies.

Authors

Mariana G. Weber, Chara J. Walters-Laird, Amir Kol, Clarissa Santos Rocha, Lauren A. Hirao, Abigail Mende, Bipin Balan, Juan Arredondo, Sonny R. Elizaldi, Smita S. Iyer, Alice F. Tarantal, Satya Dandekar

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Figure 1

MSC promotes peripheral virus reduction with clearance from effector sites and restoration of CD4+ T cells in the gut lymphoid follicles.

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MSC promotes peripheral virus reduction with clearance from effector sit...
(A) Study design and sample collection. Nx indicates necropsy. (B) Viral RNA loads were measured in longitudinal plasma samples at 0, 14, 28, 42, 56, and 70 days after infection by qPCR (SIV+ n = 7, SIV+MSC+ n = 5). (C and D) Detection of SIV RNA in ileum and MsLNs by in situ RNA hybridization. Representative images show SIV RNA in villi and lymphoid follicle (LF) during chronic infection (RNAscope, 10× magnification). RNA visualized as a chromogenic magenta stain; 100× magnification of villi showing the presence of virus in SIV+ animals and its absence in SIV+MSC+, and GC in ileal tissue showing individual infected cells (SIV+) and viral trapping on follicular DC network (SIV+MSC+). Inspection of MsLNs demonstrated well-developed GCs in the SIV+MSC+ group with SIV viral RNA localizing preferentially within GCs compared with SIV+ animals. Magnification 10× and 100×. Scale bars: 250 μm and 25 μm. (E and F) Dual in situ RNA hybridization and IHC analysis of MsLN of SIV+ and SIV+MSC+, showing viral RNA (red) and T cells (green). Magnification 20×. Scale bars: 50 μm. (G) Shown are longitudinal percentages of CD4+ T cells in the gut cells after gating on lymphocytes, singlets, live cells, CD45+, and CD3+ T cells (SIV+ n = 7 and SIV+MSC+ n = 5). (H and I) Percentage of CD4+ and CD8+ T cells in MsLNs (SIV– n = 5, SIV+ n = 7, and SIV+MSC+ n = 5) at 70 days after infection. Data represent the mean (± SEM) for each time point. Significance was determined using the Mann-Whitney U test (B and G) or 1-way ANOVA with Holm-Sidak post hoc testing for multiple comparisons (H and I). *P < 0.05 and **P ≤ 0.01. Gray arrow represents first MSC administration.