HIV-1 Vpr is targeted for degradation by autophagy

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.