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.
Highlights
The Vpr protein encoded by the human Immunodeficiency virus type 1 (HIV-1), formerly named Viral Protein R, is associated with replication efficiency and cytopathogenicity of the virus [1,2]
It is important to highlight that Vpr is one of the HIV-1 virion-associated proteins, reaching more than 700 molecules per virion; approximately 1:7 compared with the 5000 Gag molecules estimated by cryo-electron microscopy (EM) and scanning transmission EM [13,14,15]
This review aims to provide a comprehensive update on the state of the art of the multiple molecular mechanisms of HIV-1 Vpr that makes it an attractive candidate for antiretroviral therapy
Summary
The Vpr protein encoded by the human Immunodeficiency virus type 1 (HIV-1), formerly named Viral Protein R, is associated with replication efficiency and cytopathogenicity of the virus [1,2]. Later studies demonstrated the important role that Vpr plays in vivo for virus spread and pathogenesis [4]. Along this line, several studies demonstrated that Vpr increases the rate of viral replication and accelerates the cytopathic effect of the virus on T cells and, more importantly, is essential for viral replication in macrophages [5,6,7]. Notwithstanding the significant progress achieved, available antiretroviral strategies are not capable of eradicating HIV in treated patients due to viral reservoirs within cells and tissues, emergence of resistant viruses and adverse effects associated with each antiviral drug class. This review aims to provide a comprehensive update on the state of the art of the multiple molecular mechanisms of HIV-1 Vpr that makes it an attractive candidate for antiretroviral therapy
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