# Attenuating Inflammation to Restore GI Tract Integrity and Reduce Viral Reservoirs During cART

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2020 · $614,002

## Abstract

PROJECT SUMMARY
Despite advances in combination antiretroviral therapy (cART), human immunodeficiency virus (HIV) infection
remains a major public health burden. Current therapeutic regimens often achieve complete viral suppression
but require lifelong adherence, as the virus quickly rebounds from tissue and cellular reservoirs following
treatment interruption. Moreover, chronic inflammation persists in cART-suppressed individuals and
contributes to comorbidities even in the absence of detectable viremia. Thus, a major goal in HIV research is
focused on approaches that lead to either sustained viral control or elimination of viral reservoirs (either a
`functional' or `sterilizing' cure), with the additional objective to develop approaches that reduce the persistent
inflammatory process that complicates disease-free remission during cART treatment.
 Recent work has highlighted the critical role of the gastrointestinal (GI) tract in HIV persistence, with the GI
tract comprising the vast majority of viral reservoirs in the body during cART. Importantly, residual systemic
inflammation observed in HIV infected, cART suppressed individuals appears driven by increased GI tract
permeability. A substantial body of research has shown a critical role for TNFα in perpetuating the pro-
inflammatory cycle that occurs with other GI disorders, such as inflammatory bowel disease. Notably, TNFα
has been shown to contribute to the pro-inflammatory milieu that is elevated in HIV infected individuals, but the
role of TNFα in GI-associated pathology during HIV disease is not well understood. We hypothesize that
persistent damage to the GI tract epithelial barrier is a major cause of residual local and systemic
inflammation in HIV infected individuals on cART, which plays an important role in viral reservoir
persistence within the GI tract, and attenuating GI tract, and systemic, inflammation will lead to
restored gut restoration, immune homeostasis and reduced reservoir persistence.
 TNFα therefore represents an attractive target for mitigating the inflammatory milieu during the chronic
phase of HIV infection. Thus, two different approaches to target TNFα will be utilized in a non-human primate
model of HIV infection, i) an FDA-approved antibody against TNFα therapy (adalimumab, Humira) and ii) a
novel small molecule inhibitor of the downstream kinase, RIPK1. The extent and characteristics of GI tract
pathology and the restoration of immune homeostasis (Aim 1) and the quantity, distribution, and characteristics
of the viral reservoir within the GI tract (Aim 2) will be evaluated throughout treatment and following the
conclusion of the experiments. Discovering a critical role for TNFα in modulating the GI manifestations of HIV
would have a significant impact on the direction of future HIV research and treatment. Moreover, use of either
a novel inhibitor that is currently in clinical development, or the re-purposing of an FDA-approved drug, as new
therapeutic modalities...

## Key facts

- **NIH application ID:** 9995018
- **Project number:** 5R01DK119945-03
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** JACOB D ESTES
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $614,002
- **Award type:** 5
- **Project period:** 2018-09-20 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9995018

## Citation

> US National Institutes of Health, RePORTER application 9995018, Attenuating Inflammation to Restore GI Tract Integrity and Reduce Viral Reservoirs During cART (5R01DK119945-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9995018. Licensed CC0.

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