# Probing the role of adenosine pathway in SIV pathogenesis

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $774,038

## Abstract

Extracellular adenosine (ADO) is a potent immunoregulatory nucleoside that limits tissue damage due to
inflammation. ADO is produced by the action of cell surface ectoenzymes (CD39/CD73) that metabolize
adenosine triphosphate (ATP) or nicotinamide adenine dinucleotide (NAD+) into adenosine monophosphate
(AMP) and then into ADO. Our NHP studies showed that, upon SIV infection, the levels of ADO in the gut tissues
are lower in models of pathogenic infection (pigtailed macaques, PTMs; which develops severe gut dysfunction
and systemic INFL upon the SIV infection) than in models of nonpathogenic infection (African green monkeys,
AGMs; which maintain an intact gut barrier and baseline levels of IA/INFL upon SIV infection). The different
CD39/CD73 expression on mucosal Tregs and contrasting ADO levels in these species with divergent
inflammatory responses to SIV support a key role of ADO in controlling IA/INFL in nonpathogenic SIV infections.
Changes in ADO levels predominately occurred in the gut, suggesting that the ADO pathway may be involved
in sparing the AGMs from developing SIV-related gut dysfunction. These findings strongly support a significant
involvement of the ADO pathway in the pathogenesis of SIV/HIV related gut dysfunction and indicate that more
focused studies aimed to harness the ADO pathway at mucosal sites of viral replication are needed. In this
project, we will directly test the hypothesis that the ADO signaling pathway plays a pivotal role in modulating the
inflammatory gut mucosal environment after SIV/HIV infection, through an intervention aimed at increasing ADO
production in a model of pathogenic SIV infection. We will administer the HIF-1α prolyl-hydroxylase inhibitor
Roxadustat to chronically SIV-infected NHPs and assess its impact on the gut integrity and on key parameters
of SIV pathogenesis. Our objectives are to assess the impact of increasing ADO signaling on (i) alleviating gut
dysfunction and systemic INFL and (ii) virus reservoirs. These innovative experiments will directly probe a new
regulatory inflammatory pathway, enabling us to decipher the mechanisms responsible for the HIV/SIV-related
gut dysfunction. As such, our studies will inform future therapeutic strategies aimed at preservation of gut integrity
and control of residual IA/INFL that are the root causes of multiple comorbidities. Finally, if successful, our
experiments may be directly translated as a new therapeutic strategy to alleviate SIV/HIV-related gut dysfunction.

## Key facts

- **NIH application ID:** 10872174
- **Project number:** 5R01AI179317-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Ivona Vasile Pandrea
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $774,038
- **Award type:** 5
- **Project period:** 2023-06-20 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10872174

## Citation

> US National Institutes of Health, RePORTER application 10872174, Probing the role of adenosine pathway in SIV pathogenesis (5R01AI179317-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10872174. Licensed CC0.

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