# New insights into the interplay between HIV and the autophagy machinery

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2022 · $386,763

## Abstract

PROJECT SUMMARY
 Autophagy is an important cellular antiviral defense mechanism that potentially affects HIV infection and
transmission. The antiviral properties of autophagy are two-fold: (i) autophagy targets virions for lysosomal
degradation and (ii) this pathway aids in antigen presentation of virus pathogens. Despite its antiviral potential,
efforts to capitalize on autophagy against HIV have been limited due to a gap in our understanding of the role of
autophagy in HIV infection. Our long-term goal is to manipulate the antiviral properties of autophagy to facilitate
HIV clearance and improve treatments. Our overall objective is to identify the molecular interactions between
HIV and the autophagy machinery. Our central hypothesis is that autophagy restricts HIV, but the virus
overcomes this block using Nef, a notorious virulence factor that mediates immune evasion. This hypothesis has
been formulated based on our published and novel work demonstrating that autophagy depletes the HIV proteins
Gag, Vif and Vpr, but only when nef is defective 17. Gag is the driver of virion assembly; Vif counteracts the
damaging effects of the restriction factor APOBEC3G; and Vpr enhances infectivity by facilitating viral
transcription and arresting cell cycle at G2. Thus, a decrease in Gag, Vif and Vpr will impact virion production
and infectivity. However, we found that Nef blocks autophagy, restoring in turn HIV proteins and particle release.
Our studies showed that Nef sequesters the autophagosome initiator BECN1 at the endoplasmic reticulum (ER)
by facilitating its association with the autophagy inhibitor BCL2. Mechanistically, we uncovered that Nef induces
BCL2 mono-ubiquitination via the E3 ligase Parkin. This post-translational modification increases BCL2's
inhibitory effect over BECN1. Hence, this activity of Nef impairs autophagosome formation. The significance for
this research is that: (i) it will address an important knowledge gap concerning the interplay between HIV and
autophagy, and will reveal how this pathway influences HIV infection and transmission; and (ii) it will provide the
basis for the design of approaches aimed at enhancing autophagy to treat HIV infection and/or improve cure
strategies. We will attain the overall objective by pursuing the following three specific aims: (1) Identify HIV
molecules vulnerable to autophagy; (2) Dissect the mechanism by which Nef blocks autophagy; and (3) Elucidate
the impact of autophagy antagonism on HIV infectivity. The proposed research is innovative because it
represents a substantive departure from the status quo by revealing that HIV critically needs Nef to counteract
autophagy restriction.

## Key facts

- **NIH application ID:** 10440528
- **Project number:** 5R01AI155012-02
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Ruth Serra Moreno
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $386,763
- **Award type:** 5
- **Project period:** 2021-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10440528

## Citation

> US National Institutes of Health, RePORTER application 10440528, New insights into the interplay between HIV and the autophagy machinery (5R01AI155012-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10440528. Licensed CC0.

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