# TRIM-directed autophagy in HIV restriction and control of inflammation

> **NIH NIH P20** · UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR · 2021 · $251,321

## Abstract

SUMMARY 
 The relative ability of cell autonomous HIV-1 restriction factors to interfere with the viral life cycle 
contributes to a host’s level of susceptibility to infection. Pharmacological enhancement of restriction factor 
efficacy would be a novel approach to treating HIV infection. However, the mechanistic basis for HIV blockage 
by restriction factors is not completely understood hampering efforts to employ restriction factor-based host 
directed therapies. The tripartite motif (TRIM) family of proteins consists of more than 70 members in humans, 
several of which have been identified as antiviral restriction factors. In this role, TRIMs can diminish viral 
replication directly by interfering with the viral life cycle or indirectly by fine tuning cellular innate immune 
responses. TRIM family member TRIM5α accomplishes both of these: first, it prevents retroviral infection of 
cells by a hitherto unexplained mechanism. Second, TRIM5α also acts as a pattern recognition receptor, 
promoting the establishment of an antiviral cellular state via the activation of inflammatory signaling pathways 
upon retroviral recognition. 
 Although TRIMs appear to employ multiple approaches in antiretroviral defense, one strikingly common 
feature among the TRIM family is that many if not all TRIMs are involved in the regulation and execution of 
autophagy. In addition to its role as a known defense mechanism against intracellular pathogens (including 
HIV-1), autophagy is also increasingly recognized as a means of reducing or fine tuning inflammation. Here, 
we propose to test the hypothesis that autophagy underlies TRIM action in protecting cells against HIV-1 
infection and in modulating the TRIM-dependent inflammatory signaling. The studies proposed here have 
several overarching goals. First, they seek to improve our understanding of the molecular mechanism whereby 
rhesus TRIM5α both regulates autophagy and directs the autophagic degradation of incoming HIV-1 capsids 
(Aim 1). Second, they will determine if modulations of the autophagy pathway affect TRIM5α-dependent 
activation of pro-inflammatory signaling upon lentiviral infection. Finally, they will address whether human 
TRIMs other than TRIM5α that restrict HIV also employ autophagy in their antiviral actions (Aim 2). We have 
assembled a team of autophagy and HIV experts to address these questions. 
 Our studies have the potential to uncover the mode of action of several known antiretroviral proteins and 
lay the groundwork for our understanding of how TRIMs as a family can both positively and negatively affect 
inflammation. We expect these studies to show that autophagy is a unifying aspect of diverse TRIM actions in 
HIV defense. Since autophagy can be pharmacologically manipulated, our findings may indicate that 
modulations of autophagy could be a therapeutic approach to dealing with TRIM-related diseases including 
HIV/AIDS. Our expertise in TRIMs and autophagy, along with the financial ...

## Key facts

- **NIH application ID:** 10249120
- **Project number:** 5P20GM121176-05
- **Recipient organization:** UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
- **Principal Investigator:** Michael Aaron Mandell
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $251,321
- **Award type:** 5
- **Project period:** 2017-09-01 → 2021-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10249120

## Citation

> US National Institutes of Health, RePORTER application 10249120, TRIM-directed autophagy in HIV restriction and control of inflammation (5P20GM121176-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10249120. Licensed CC0.

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