Year: 2024
Type: article
Abstract: HIV-1 Vpr promotes efficient spread of HIV-1 from macrophages to T cells by transcriptionally downmodulating restriction factors that target HIV-1 Envelope protein (Env). Here we find that Vpr induces broad transcriptomic changes by targeting PU.1, a transcription factor necessary for expression of host innate immune response genes, including those that target Env. Consistent with this, we find silencing PU.1 in infected macrophages lacking Vpr rescues Env. Vpr downmodulates PU.1 through a proteasomal degradation pathway that depends on physical interactions with PU.1 and DCAF1, a component of the Cul4A E3 ubiquitin ligase. The capacity for Vpr to target PU.1 is highly conserved across primate lentiviruses. In addition to impacting infected cells, we find that Vpr suppresses expression of innate immune response genes in uninfected bystander cells, and that virion-associated Vpr can degrade PU.1. Together, we demonstrate Vpr counteracts PU.1 in macrophages to blunt antiviral immune responses and promote viral spread.
Source: Nature Communications
Institutions: University of Michigan, University of Pennsylvania
Language: English
Topic: HIV Research and Treatment
Subfield: Virology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,790
Funders: U.S. Department of Health and Human Services, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, University of Michigan, National Institutes of Health, National Institute on Drug Abuse, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases
Awards: Single-cell multi-omic analysis of opioid-mediated HIV disease pathogenesis, G2834129054, G3080159220, G3329677587, G3707583585, Cellular Biotechnology Training Program (CBTP), G471189809, University of Michigan Postbaccalaureate Research Education Program (UM PREP), G5196924089, Cellular and Molecular Biology at Michigan, Investigating the Role of Innate Immune Factors in Restricting HIV Spread in Macrophages, G6690226117, HIV evasion of the innate immune response, G8759427388, Integrative Single-Cell Analysis of Transcriptome, Epigenome, and Lineage in HIV Latency and Activation, Cellular Biotechnology Training Program (CBTP) - Years 31-35
OpenAlex ID: W4400199045