# Mesenchymal stem/stromal cells to enhance cytotoxic T cell immunity during HIV infection

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2024 · $320,833

## Abstract

Multipotent stem/stromal cells (MSC) are promising candidate therapeutics for HIV infection, given their potent
immunomodulatory properties and wide safety margins. It remains unknown if MSC can reverse CD8 T cell
exhaustion and promote trafficking of CD8 T cells into privileged sites during chronic HIV infection. Thus, there
is a critical need to determine whether CD8 T cell exhaustion can be therapeutically targeted by MSC. Our
long-term goal is to define mechanisms of MSC-induced immune-modulation during chronic viral infections so
that improved therapeutic strategies be developed. Our overall objective in this application is to determine if
MSC treatment can enhance viral clearance via reversal of exhausted CD8 T cells in chronic SIV-infected
macaques. Our central hypothesis is that systemic infusions of allogeneic MSC enhance viral clearance in
ART-naïve, and delay viral rebound upon ART interruption in ART-treated SIV-infected macaques, via reversal
of CD8 T cell exhaustion and infiltration of privileged sites. The rationale that underlies the proposed research
is that CD8 T cell exhaustion and viral sequestration are major mechanisms of HIV viral persistence that may
be targeted with MSC treatment. To test our hypothesis we will use the SIV-infected non-human primate model
of AIDS. SIV-infected animals will be treated with a combination of ART and/or MSC and samples from
peripheral blood, gut tissue, and lymph nodes will be collected during necropsies. The central hypothesis will
be tested by pursuing two specific aims: 1) Determine the impact of MSC treatment on exhausted CD8 T cell
populations in rhesus macaques chronically infected with SIV. Our working hypothesis is that MSC treatment
reverses CD8 T cell exhaustion that is driven by chronic SIV infection. We will sort CD8 T cells from blood, gut
tissue, and lymph nodes and perform single-cell RNAseq analysis, multi-color flow cytometry, and ex-vivo
stimulation assays. 2) Determine the impact of MSC treatment on CD8 T cell trafficking into lymphoid follicles
in rhesus macaques chronically infected with SIV. Our working hypothesis is that MSC treatment in chronic
SIV-infected macaques enhances CXCR5+/CD8 T cell trafficking into B-cell follicles. We will determine the
micro-anatomical distribution and phenotype of SIV-specific CD8 T cells and viral reservoirs in gut tissue and
lymph nodes via in situ MHC-tetramer, and immunohistochemistry staining, and confocal microscopy. The
research proposed in the application is innovative because it explores a new therapeutic paradigm of targeting
multiple mechanisms of HIV persistence concurrently on multiple mechanistic levels. The proposed research is
significant because HIV/AIDS remains a significant global health crisis that is partially driven by viral
persistence despite effective antiretroviral therapy and suppression of viral replication. Moreover, as CD8 T cell
exhaustion has been implicated in the pathogenesis of multiple other chronic vir...

## Key facts

- **NIH application ID:** 10754968
- **Project number:** 5R21OD032351-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Amir Kol
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $320,833
- **Award type:** 5
- **Project period:** 2022-12-15 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10754968

## Citation

> US National Institutes of Health, RePORTER application 10754968, Mesenchymal stem/stromal cells to enhance cytotoxic T cell immunity during HIV infection (5R21OD032351-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10754968. Licensed CC0.

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