The HIV-1 Vpr Protein: A Multifaceted Target for Therapeutic Intervention

Abstract

The human immunodeficiency virus type 1 (HIV-1) Vpr protein is an attractive target for antiretroviral drug development. The conservation both of the structure along virus evolution and the amino acid sequence in viral isolates from patients underlines the importance of Vpr for the establishment and progression of HIV-1 disease. While its contribution to virus replication in dividing and non-dividing cells and to the pathogenesis of HIV-1 in many different cell types, both extracellular and intracellular forms, have been extensively studied, its precise mechanism of action nevertheless remains enigmatic. The present review discusses how the apparently multifaceted interplay between Vpr and host cells may be due to the impairment of basic metabolic pathways. Vpr protein modifies host cell energy metabolism, oxidative status, and proteasome function, all of which are likely conditioned by the concentration and multimerization of the protein. The characterization of Vpr domains along with new laboratory tools for the assessment of their function has become increasingly relevant in recent years. With these advances, it is conceivable that drug discovery efforts involving Vpr-targeted antiretrovirals will experience substantial growth in the coming years.

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

“…The R77A/Q change and the R80A mutations do not disrupt Vpr's ability to degrade PHF13. Notably, R77A/Q and R80A are associated with induction of cell death, whereas only R80A has lost the capacity to arrest cells in G 2 [ 12 ]. We corroborated these results by a transcomplementation approach, in which virus producing 293T cells are transfected to co-express Vpr.…”

“…Similar to the L64P variant, L64-68A is not incorporated into virions [ 9 ] and hence defective in PHF13 degradation. Mutants L22A and E21/24Q do not oligomerize and are impaired in inducing PARP1 translocation [ 9 , 12 ]. Nevertheless, both mutants degraded PHF13 ( figure 4 b ), suggesting that Vpr-mediated PHF13 degradation is not coupled to these functions.…”

“…Vpr enhances HIV-1 replication in human lymphoid tissue (HLT) [ 8 ], non-activated CD4 + T cells [ 9 ], macrophages [ 10 ] and some immortalized T cell lines [ 11 ]. This enhancement could be related to its ability to increase nuclear import of the HIV-1 pre-integration complex, activation of various transcription factors including NFAT (nuclear factor of activated T cells) and a direct stimulation of HIV-1 LTR transactivation [ 7 , 12 ]. One of the best-investigated Vpr phenotypes is its ability to induce a G 2 cell cycle arrest, which is related to the association of Vpr with a larger ubiquitin ligase complex composed of VPRBP (Vpr binding protein or DCAF), DNA damage-binding protein 1 (DDB1) and the ubiquitin ligase cullin 4A (CUL4A) [ 13 ].…”

Impact of HIV-1 Vpr manipulation of the DNA repair enzyme UNG2 on B lymphocyte class switch recombination

“…The here described potential evasion of HIV-1 from antibody class switching by the Vpr-mediated UNG2 degradation in bystander B-cells, paves the way towards a better understanding of HIV-related humoral de ciencies and suggests the ablation of Vpr coding sequences from vaccine strategies. In addition, considering the extensive proteome remodeling Vpr can induce in infected cells 94 and various bystander cells, as well as pharmacological strategies aimed to interfere with its multiple functions 95,96 , Vpr has reemerged as an attractive target for HIV disease treatment 97 .…”

Single molecule studies of DNA bending, looping and compacting proteins using optical tweezers and atomic force microscopy

“…is about the size of the large cross-section of the conical mature HIV capsid. Quantitative understanding of Vpr functions will pave the way for antiviral therapeutics to target efficiently the virus and reduce the proliferation of HIV-1 (241). To understand and elucidate the specific functions of Vpr, we combine single molecule stretching, atomic force microscopy (AFM) and transmission electron microscopy with quantitative image processing and analysis.…”