Characterization of the Molecular Determinants of Primary HIV-1 Vpr Proteins: Impact of the Q65R and R77Q Substitutions on Vpr Functions

Abstract

Although HIV-1 Vpr displays several functions in vitro, limited information exists concerning their relevance during infection. Here, we characterized Vpr variants isolated from a rapid and a long-term non-progressor (LTNP). Interestingly, vpr alleles isolated from longitudinal samples of the LTNP revealed a dominant sequence that subsequently led to diversity similar to that observed in the progressor patient. Most of primary Vpr proteins accumulated at the nuclear envelope and interacted with host-cell partners of Vpr. They displayed cytostatic and proapoptotic activities, although a LTNP allele, harboring the Q65R substitution, failed to bind the DCAF1 subunit of the Cul4a/DDB1 E3 ligase and was inactive. This Q65R substitution correlated with impairment of Vpr docking at the nuclear envelope, raising the possibility of a functional link between this property and the Vpr cytostatic activity. In contradiction with published results, the R77Q substitution, found in LTNP alleles, did not influence Vpr proapoptotic activity.

SLX4-SLX1 Protein-independent Down-regulation of MUS81-EME1 Protein by HIV-1 Viral Protein R (Vpr)

“…This suggests the function of MUS81-EME1 down-regulation by Vpr is independent of its activity in G 2 arrest. An analysis of Vpr Q65R, another mutant defective in G 2 arrest (22,25,28,37), further supports this conclusion (Fig. 5, E and F).…”

“…In this case, down-regulation of the unknown factor(s) would activate ATR-mediated checkpoint signaling and induce G 2 arrest. In line with this hypothesis, mutagenesis studies have shown that a Vpr mutant with reduced DCAF1 binding, Q65R, lacks the ability to induce G 2 arrest (22,25,28,37). Furthermore, single mutation at Arg-80 (R80A) results in abrogation of Vpr-mediated G 2 cell cycle arrest without affecting DCAF1 interaction (10, 22, 25, 38 -40).…”

HIV-1 Vpr degrades the HLTF DNA translocase in T cells and macrophages

“…A similar reversion has been observed in a laboratory worker accidentally contaminated with a vpr-deficient strain of HIV-1 (15,16). Several studies also reported mutations in the vpr gene in long-term nonprogressor (LTNP) patients (17)(18)(19)(20). Several lines of evidence indicate that Vpr interferes with DNA repair pathways (21).…”

Vpr Enhances Tumor Necrosis Factor Production by HIV-1-Infected T Cells

“…A similar reversion was observed in a laboratory worker accidentally contaminated with a vpr-deficient strain of HIV-1 (36,37). Several researchers also reported mutations in the vpr gene in patients who were long-term nonprogressors (LTNP) (38)(39)(40)(41). Many activities have been described for Vpr.…”