HIV-1 Vpr Reprograms CLR4 ^DCAF1 E3 Ubiquitin Ligase to Antagonize Exonuclease 1-Mediated Restriction of HIV-1 Infection

Abstract

HIV-1 polymerase reverse transcribes the viral RNA genome into imperfectly double-stranded proviral DNA, containing gaps and flaps, for integration into the host cell chromosome. HIV-1 reverse transcripts share characteristics with cellular DNA replication intermediates and are thought to be converted into fully double-stranded DNA by cellular postreplication DNA repair enzymes. Therefore, the finding that the HIV-1 accessory protein Vpr antagonizes select postreplication DNA repair enzymes that can process HIV-1 reverse transcripts has been surprising. Here, we show that one such Vpr-antagonized enzyme, exonuclease 1, inhibits HIV-1 replication in T cells. We identify exonuclease 1 as a member of a new class of HIV-1 restriction factors in T cells and propose that certain modes of DNA “repair” inhibit HIV-1 infection.

Distinct MCM10 Proteasomal Degradation Profiles by Primate Lentiviruses Vpr Proteins

“…Particularly, the ubiquitin dependent degradation pathway is one of the attractive machineries manipulated by multiple accessory proteins, such as, Vif, Vpu, and Vpx, of primate lentiviruses. Predominantly, Vpr was found to invoke increasingly numerous host factors for proteasome dependent degradation, such as MCM10, MUS81, helicase-like transcription factor (HLTF), Exonuclease 1 (Exo1), and histone deacetylases (HDACs) [35][36][37]47,48]. Interestingly, these cellular targets also respond to DNA damage from viruses or other environmental stimulants.…”

“…Vpr may possibly load Exo1 onto the E3 ligase complex and remodel the post-replication DNA repair machinery independently of PCNA bridging. However, the correlation between Exo1 depletion by Vpr and DNA damage response remains unknown [48,49].…”

Global post-translational modification profiling of HIV-1-infected cells reveals mechanisms of host cellular pathway remodeling

“…6,056 proteins could be quantified in sufficient biological replicates for statistical analysis. Protein abundance analysis recapitulated effects for several factors that have been reported to be degraded by HIV-1 infection, including BST2/tetherin that is degraded by Vpu, HLTF that is degraded by Vpr, and two members of the PP2A B56 variable regulatory subunit family (peptides identified could not distinguish delta and gamma family members) -that are degraded by Vif ( Figure 3B) (Laguette et al, 2014;Lahouassa et al, 2016a;Lv et al, 2018;Yan et al, 2018).This analysis also recapitulated stabilization of β -catenin that has been reported to be a result of sequestration of the Cullin-1/Skp1/βTrCP ubiquitin ligase by the Vpu protein (Besnard-Guerin et al, 2004).…”

“…The HIV-1 Vpr protein also binds to CRL4 DCAF1 , but it does not share SAMHD1 and HUSH inactivation functions with HIV-2 Vpx. Several Vpr-CRL4 DCAF1 substrates have been identified including the uracil N-glycosylase 2 (UNG2), Mus81 (part of the SLX4 complex), helicase-like transcription factor (HLTF), exonuclease 1 (EXO1), and Tet DNA dioxygenase 2 (TET2) (Laguette et al, 2014;Lahouassa et al, 2016;Lv et al, 2018;Yan et al, 2018). However, only TET2 has been demonstrated to rescue a replication defect of Vpr-deficient viral replication in primary monocyte-derived macrophages and the rescue was only partial (Wang and Su, 2019).…”

Cell Cycle Regulation in Macrophages and Susceptibility to HIV-1

“…Vpr/Vif-mediated G2/M arrest studies have been performed in cycling cells including T cell lines [107,109,111,113,121,122], THP-1 [99], Hela and HEK293 [98,113,122], and primary CD4 T cells [120,123].…”