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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\u20133, 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\u201386, 93\u201394 in NL4\u20133 Vpr as responsible for its susceptibility to autophagy. Importantly, differences between NL4\u20133 and TFV Vpr proteins at these positions impact their interaction with the autophagy receptors NDP52, SQSTM1\/p62 and TAX1BP1. By engineering NL4\u20133 molecular clones harboring either autophagy-sensitive or -resistant\n                    <jats:italic>vpr<\/jats:italic>\n                    , we found that in 2D and 3D\n                    <jats:italic>in vitro<\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1014020","type":"journal-article","created":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T18:38:46Z","timestamp":1772476726000},"page":"e1014020","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["HIV-1 Vpr is targeted for degradation by autophagy"],"prefix":"10.1371","volume":"22","author":[{"given":"Yuexuan","family":"Chen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susanne","family":"Klute","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anju","family":"Bansal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Konstantin Maria Johannes","family":"Sparrer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1923-6414","authenticated-orcid":true,"given":"Ruth","family":"Serra-Moreno","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2026,3,2]]},"reference":[{"issue":"22","key":"ppat.1014020.ref001","doi-asserted-by":"crossref","first-page":"2861","DOI":"10.1101\/gad.1599207","article-title":"Autophagy: process and function","volume":"21","author":"N Mizushima","year":"2007","journal-title":"Genes Dev"},{"issue":"3","key":"ppat.1014020.ref002","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1089\/ars.2013.5371","article-title":"An overview of autophagy: morphology, mechanism, and regulation","volume":"20","author":"KR Parzych","year":"2014","journal-title":"Antioxid Redox 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