Tumultuous relationship between the human immunodeficiency virus type 1 viral infectivity factor (Vif) and the human APOBEC-3G and APOBEC-3F restriction factors

Abstract

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 Pr55(Gag), by enhancing the efficiency of the reverse transcription process, and by inhibiting the enzymatic activities of hA3G and hA3F.

FIG. 1.

Schematic representation of HIV-1 Vif domains required for interactions with viral and cellular molecules. The N-terminal region of Vif is green, the central zinc binding domain is orange, and the C-terminal region is red, turquoise, and Matisse blue.

FIG. 2.

Electron micrographs of WT and Δvif HIV-1 virions from nonpermissive (H9 and HUT78) or semipermissive (CEMx174) cells. (Panels for CEMx174, HUT78, and H9 cells are adapted from references , , and , respectively, with permission.)

FIG. 3.

Schematic representation of Vif and hA3G functions in HIV-1 assembly and replication. During viral particle production, Vif is found in the cytoplasm of infected cells and is encapsidated in small amounts into virions. Vif neutralizes hA3G and hA3F in virus-producing cells by different mechanisms. (1) Vif has been shown to impair the translation of hA3G mRNA, probably through an mRNA-binding mechanism. (2) Vif binding to hA3G protein recruits an E3 ubiquitin ligase that mediates the polyubiquitylation of hA3G and its degradation. (3) Vif competes with hA3G for binding to viral components like the nucleocapsid domain of Gag and/or viral genomic RNA. Taken together, these three different actions of Vif on translation, degradation, and packaging not only deplete hA3G from virus-producing cells but also prevent hA3G from being incorporated in virions. (4 and 5) Intracellular Vif may also influence viral assembly through the modulation of viral protease-mediated cleavage of Gag precursors (4) and its chaperoning activities (5), thus allowing late events such as precursor maturation, initiation of reverse transcription, and RNA dimer maturation to occur after viral budding. (6) Finally, Vif might be able to directly inhibit the activity of the few hA3G molecules that are packaged in WT virions.

FIG. 4.

Multiple antiviral mechanisms of virion-incorporated and endogenous hA3G. In the absence of Vif, hA3G is efficiently incorporated into budding viruses. After liberation of the viral capsid into a new (nonpermissive) target cell, hA3G impedes reverse transcription and integration in a deaminase-independent antiviral action, probably through its RNA-binding properties. Once reverse transcription has started, hA3G mediates the extensive deamination of dC to dU during minus-strand DNA synthesis. This enzymatic reaction blocks HIV-1 replication due to (i) the accumulation of dG-to-dA hypermutations in the synthesized plus-stranded viral DNA (giving rise to aberrant proteins) and (ii) the degradation of viral DNA, because the U-rich DNA can be recognized by the cellular repair machinery (uracil DNA glycosylase and apurinic-apyrimidic endonuclease). Endogenous h3AG also functions as a potent restriction factor for HIV-1 in resting CD4⁺ T cells. hA3G exist as HMM and LMM complexes. Only the LMM complexes function as a postentry restriction factor by blocking the accumulation of reverse transcripts of incoming viruses. HMM complexes impair the transposition of Alu elements by sequestering Alu RNA transcripts away from the nuclear transposition machinery.