# HIV-1 Vpr is targeted for degradation by autophagy

## TL;DR

The HIV-1 protein Vpr is targeted for destruction by the cell's autophagy system, and its susceptibility to this process affects how the virus spreads.

## Contribution

Identifies HIV-1 Vpr as a novel autophagy target and shows that Vpr susceptibility to autophagy impacts HIV-1 spread.

## Key findings

- HIV-1 Vpr from the NL4–3 strain is targeted for autophagy, while Vpr from transmitted/founder viruses is resistant.
- Specific residues in NL4–3 Vpr affect its interaction with autophagy receptors like NDP52, SQSTM1/p62, and TAX1BP1.
- Viruses with autophagy-sensitive Vpr show reduced spread in 2D and 3D in vitro systems.

## Abstract

Autophagy is part of the innate immune arsenal to fight viruses, including HIV-1. We previously reported that HIV-1 Gag is targeted for autophagy-mediated degradation. Here, we identify HIV-1 Vpr, an important virulence factor, as an autophagy target in HIV-1 NL4–3, a lab adapted molecular clone. Notably, Vpr proteins from a collection of transmitted/founder viruses (TFVs) were resistant to autophagy. Based on this observation, we identified residues at positions 37, 45, 77, 83–86, 93–94 in NL4–3 Vpr as responsible for its susceptibility to autophagy. Importantly, differences between NL4–3 and TFV Vpr proteins at these positions impact their interaction with the autophagy receptors NDP52, SQSTM1/p62 and TAX1BP1. By engineering NL4–3 molecular clones harboring either autophagy-sensitive or -resistant vpr, we found that in 2D and 3D in vitro systems virus spread was significantly reduced for the virus carrying autophagy-sensitive Vpr. In conclusion, our study identifies Vpr as a novel autophagy target and suggests that Vpr susceptibility to autophagy impacts HIV-1 spread.

Autophagy is a cellular process essential for homeostasis, but also serves as a potent defense mechanism against intracellular pathogens, including viruses. We previously reported that the HIV-1 structural protein Gag (precursor of the virus capsid) is targeted by autophagy for elimination. However, the virus has evolved the accessory protein Nef to antagonize autophagy. In this study, we identify the HIV-1 accessory protein Vpr as another autophagy target and uncovered the autophagy receptors SQSTM1, TAX1BP1 and NDP52 as responsible for targeting Vpr to autophagosomes. Remarkably, we found that Vpr proteins of transmitted/founder viruses are resistant to autophagy, suggesting that autophagy resistance of Vpr might promote virus spread.