Tumultuous Relationship between the Human Immunodeficiency Virus Type 1 Viral Infectivity Factor (Vif) and the Human APOBEC-3G and APOBEC-3F Restriction Factors

Abstract

SUMMARY The viral infectivity factor (Vif) is dispensable for human immunodeficiency virus type 1 (HIV-1) replication in so-called permissive cells but is required for replication in nonpermissive cell lines and for pathogenesis. Virions produced in the absence of Vif have an aberrant morphology and an unstable core and are unable to complete reverse transcription. Recent studies demonstrated that human APOBEC-3G (hA3G) and APOBEC-3F (hA3F), which are selectively expressed in nonpermissive cells, possess strong anti-HIV-1 activity and are sufficient to confer a nonpermissive phenotype. Vif induces the degradation of hA3G and hA3F, suggesting that its main function is to counteract these cellular factors. Most studies focused on the hypermutation induced by the cytidine deaminase activity of hA3G and hA3F and on their Vif-induced degradation by the proteasome. However, recent studies suggested that several mechanisms are involved both in the antiviral activity of hA3G and hA3F and in the way Vif counteracts these antiviral factors. Attempts to reconcile the studies involving Vif in virus assembly and stability with these recent findings suggest that hA3G and hA3F partially exert their antiviral activity independently of their catalytic activity by destabilizing the viral core and the reverse transcription complex, possibly by interfering with the assembly and/or maturation of the viral particles. Vif could then counteract hA3G and hA3F by excluding them from the viral assembly intermediates through competition for the viral genomic RNA, by regulating the proteolytic processing of Pr55Gag, by enhancing the efficiency of the reverse transcription process, and by inhibiting the enzymatic activities of hA3G and hA3F.

HIV-1 Vif-mediated ubiquitination/degradation of APOBEC3G involves four critical lysine residues in its C-terminal domain

“…As Vif expression was increased, the steady state levels of intracellular WT A3G were decreased (Cell, lanes 2-6), while the levels of S-A3G protein were not affected (Cell, lanes [8][9][10][11][12]. Concomitant with the decrease in protein levels of intracellular WT A3G, its incorporation into virions was also reduced (Virus, lanes 2-6), while under identical experimental conditions, S-A3G packaging was not significantly affected (Virus, lanes [8][9][10][11][12]). These findings demonstrate that S-A3G incorporation into HIV-1 virions is independent of Vif.…”

Properties and functions of the nucleocapsid protein in virus assembly

“…130 Recent studies revealed that Vif counteracts the human restriction factors APOBEC-3G (hA3G) and APOBEC-3F (hA3F) that have strong anti-HIV-1 activity. APOBEC3G is incorporated in HIV-1 virions 131 in an NC dependent manner.…”

Un facteur de transcription se fait complice du VIH-1 pour détruire les défenses cellulaires

“…Les deux publications parues dans Nature [4,5] démontrent que CBF- fait partie du complexe E3 ubiquitine ligase comprenant la Cul-5, Rbx2, Elo-C et Elo-B. Cependant, la fixation de CBF- à ce complexe requiert Vif, ce qui indique que CBF- n'est pas un constituant [2][3][4][5][6]. Quels sont les facteurs présents dans le sperme responsables de cet effet ?…”

“…Plusieurs facteurs de restriction inhibant la réplication des rétrovirus, dont les virus de l'immunodéficience humaine de types 1 et 2 (VIH-1, VIH-2), ont ainsi été identifiés : TRIM5 (tripartite motif-containing protein 5), la téthérine, SAMHD1 (SAM domain and HD domain 1), et plusieurs membres de la famille des cytidines désaminases APOBEC-3 (apolipoprotein B mRNAediting, enzyme-catalytic, polypeptide-like 3) [1][2][3]. Parmi ces derniers, A-3G et A-3F, qui sont exprimés dans les cellules cibles naturelles des VIH-1 et VIH-2, sont les plus importants [1,3]. Les rétrovirus ont cependant acquis la capacité de contourner ces facteurs de restriction.…”

“…Les rétrovirus ont cependant acquis la capacité de contourner ces facteurs de restriction. Certains ont développé des protéines dites accessoires dans ce seul but : c'est le cas du facteur d'infectiosité viral (Vif) et de la protéine virale U (Vpu) des VIH-1 et VIH-2, ainsi que de la protéine virale X (Vpx) du VIH-2, qui contrecarrent respectivement A-3C/3DE/3F/3G/3H [1,3], la téthérine [1] et SAMHD1 [2]. La neutralisation des facteurs de restriction par les rétrovirus implique très souvent le détournement de la voie de dégradation des protéines cellulaires par le protéasome en réponse à leur polyubiquitination.…”