HIV1‐viral protein R (Vpr) mutations: associated phenotypes and relevance for clinical pathologies

Abstract

Over the last 30 years, research into HIV has advanced the knowledge of virus genetics and the development of efficient therapeutic strategies. HIV-1 viral protein R (Vpr) is a specialized and multifunctional protein that plays important roles at multiple stages of the HIV-1 viral life cycle. This protein interacts with a number of cellular and viral proteins and with multiple activities including nuclear transport of the pre-integration complex (PIC) to the nucleus, transcriptional activation, cell cycle arrest at G2/M transition phase and induction of cell death via apoptosis. Specifically, Vpr has been shown to control many host cell functions through a variety of biological processes and by interaction with several cellular pathways. The different functions of Vpr may enhance viral replication and impair the immune system in HIV-1 infected patients. Importantly, functional defects induced by mutations in the Vpr protein correlate with slow disease progression of HIV-infected patients. Vpr is also associated with other concomitant pathologies developed by these patients, which may lead it to be considered as a potential novel therapeutic target. This review will focus on HIV-1 Vpr, mainly on the importance of its structural mutations on the progression of HIV infection, associated phenotypes and relevance for clinical pathologies. Copyright © 2016 John Wiley & Sons, Ltd.

Dual role of the chromatin-binding factor PHF13 in the pre- and post-integration phases of HIV-1 replication

“…This block is alleviated by Vpr-mediated PHF13 depletion. Of note, the multitude of Vpr effects on several cellular processes [ 7 , 12 , 71 ] could be explained by the depletion of PHF13 and its emerging role in transcriptional regulation and co-transcriptional splicing [ 22 ].…”

Differential CXCR4 expression on hematopoietic progenitor cells versus stem cells directs homing and engraftment

“…Three point mutations were introduced: a Q65R mutation that abrogates its binding to DCAF and is the primary event that triggers a change in the cellular proteome of viral particle-delivered VPR, including depletion of cell cycle regulatory proteins and proteins involved in DDR (36), and R77Q and W54R point mutations, which further prevent its cytotoxic activities and reduce its stability. These are mutations were seen in long-term nonprogressors with HIV infection (37,40,65). This VPR MT that retains its ability to bind gag (the LV capsid protein) but lacks VPR-associated cytotoxicity was then fused to CXCR4 using the HIV-1 PCS (38) so that CXCR can be cleaved from VPR MT by the protease present in the LV particle.…”

The influence of viral protein R amino acid substitutions on clinical outcomes in people living with HIV: A systematic review

“…Overall, the structure of Vpr may seem similar between HIV-1 subtypes (Figure 2), it is known that the alteration of specific amino acids or the substitutions of amino acids at specific positions within Vpr may significantly alter its function. 53 As examples of these, mutations (R36W, I64E, L67A, and I70S) in αhelix residues result in a total inability of Vpr to oligomerize at the nuclear envelope. 54 In addition, the deletion of the amino acids of the SRIG sequence (between amino acids 79 and 82) or mutation of all arginine's in the C-terminal domain prevented G2 arrest by Vpr.…”

“…Despite several studies investigating Vpr amino acids' variation in PLWH, 53,56 there is no clear consensus on which amino acid substitutions are most commonly associated with the pathophysiology (disease progression, neurological outcomes and treatment efficacy) of HIV-1 in PLWH. Therefore, this systematic review aimed at reviewing all literature on this topic to identify the key Vpr amino acid substitutions associated with HIV-1 pathophysiology in PLWH.…”