Dual Functionality of HIV-1 Vif in APOBEC3 Counteraction and Cell Cycle Arrest

Abstract

Accessory proteins are a key feature that distinguishes primate immunodeficiency viruses such as human immunodeficiency virus type I (HIV-1) from other retroviruses. A prime example is the virion infectivity factor, Vif, which hijacks a cellular co-transcription factor (CBF-β) to recruit a ubiquitin ligase complex (CRL5) to bind and degrade antiviral APOBEC3 enzymes including APOBEC3D (A3D), APOBEC3F (A3F), APOBEC3G (A3G), and APOBEC3H (A3H). Although APOBEC3 antagonism is essential for viral pathogenesis, and a more than sufficient functional justification for Vif’s evolution, most viral proteins have evolved multiple functions. Indeed, Vif has long been known to trigger cell cycle arrest and recent studies have shed light on the underlying molecular mechanism. Vif accomplishes this function using the same CBF-β/CRL5 ubiquitin ligase complex to degrade a family of PPP2R5 phospho-regulatory proteins. These advances have helped usher in a new era of accessory protein research and fresh opportunities for drug development.

Human APOBEC3 Variations and Viral Infection

“…The HIV-1 protein Vif counteracts the antiviral activity of APOBEC3 enzymes. Vif binds to APOBEC3 enzymes and mediates their ubiquitination by the cellular Cullin5 E3-ubiquitin ligase, followed by their proteasomal degradation [ 4 , 21 , 22 , 23 , 24 ]. The counteraction ability of Vif depends on both the type of APOBEC3 enzymes and the variations within Vif.…”

Defective HIV-1 genomes and their potential impact on HIV pathogenesis

“…Intrinsic host defenses and anti-viral restriction factors limit replication and reverse transcription efficiency contributing to the generation of defective HIV genomes. APOBEC 3G, a cytosine deaminase, targets single-stranded DNA intermediates and promotes HIV-1 hypermutation by inducing guanine-to-adenine changes during the process of reverse transcription [59][60][61][62][63]. Sterile Alpha Motif-and HD-domain containing protein 1 (SAMHD1), a host viral restriction factor which reduces the concentration of intracellular nucleotides in resting CD4+ T cells and myeloid cells, limiting the efficiency and completion of reverse transcription [64][65][66][67].…”

PP2A Phosphatase as an Emerging Viral Host Factor

“…Although mostly known for its ability to target APOBEC3 restriction factors for proteasomal degradation ( Desimmie et al., 2014 ; Harris and Dudley, 2015 ), intense studies on the HIV-1 Vif accessory protein revealed that the cell cycle arrest induced by Vif occurs through its targeted degradation of B56 ( Greenwood et al., 2016 ; Marelli et al., 2020 ; Nagata et al., 2020 ; Salamango and Harris, 2020 ). Interestingly, although Vif does not encode an LxxIxE SLiM motif, co-expression of an LxxIxE-like peptide inhibitor known to outcompete B56 binders reduced degradation of B56 in a dose-dependent manner ( Salamango et al., 2020 ) suggesting that Vif recognition by B56 involves residues surrounding the LxxIxE SLiM binding pocket.…”