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

Daniel J Salamango,Reuben S Harris

doi:10.3389/fmicb.2020.622012

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.

Highlights

It has been nearly 40 years since the discovery that acquired immune deficiency syndrome (AIDS) is caused by a retrovirus named human immunodeficiency virus type I (HIV-1) (Barré-Sinoussi et al, 1983; Gallo et al, 1984; Popovic et al, 1984)
One of the major questions following the discovery of the VifAPOBEC3 interaction was how can a relatively small viral protein (∼20 kDa) interact with four restrictive APOBEC3 enzymes, recruit CBF-β, nucleate the formation of an E3ubiquitin ligase complex, and induce G2/M cell cycle arrest? Remarkably, it has become apparent that each Vif-substrate pairwise combination utilizes largely distinct, and genetically separable, interaction surfaces (Figure 2D)
Genetic studies established that Vif-induced G2/M arrest requires both CBF-β and the same E3-ubiquitin ligase complex utilized for APOBEC3 degradation (DeHart et al, 2008; Du et al, 2019)

Summary

Introduction

It has been nearly 40 years since the discovery that acquired immune deficiency syndrome (AIDS) is caused by a retrovirus named human immunodeficiency virus type I (HIV-1) (Barré-Sinoussi et al, 1983; Gallo et al, 1984; Popovic et al, 1984). One of the major questions following the discovery of the VifAPOBEC3 interaction was how can a relatively small viral protein (∼20 kDa) interact with four restrictive APOBEC3 enzymes (five in total), recruit CBF-β, nucleate the formation of an E3ubiquitin ligase complex, and induce G2/M cell cycle arrest (discussed in further detail below)?

Results

Conclusion