Research Article: Towards Inhibition of Vif-APOBEC3G Interaction: Which Protein to Target?

Date Published: September 21, 2010

Publisher: Hindawi Publishing Corporation

Author(s): Iris Cadima-Couto, Joao Goncalves.


APOBEC proteins appeared in the cellular battle against HIV-1 as part of intrinsic cellular immunity. The antiretroviral activity of some of these proteins is overtaken by the action of HIV-1 Viral Infectivity Factor (Vif) protein. Since the discovery of APOBEC3G (A3G) as an antiviral factor, many advances have been made to understand its mechanism of action in the cell and how Vif acts in order to counteract its activity. The mainstream concept is that Vif overcomes the innate antiviral activity of A3G by direct protein binding and promoting its degradation via the cellular ubiquitin/proteasomal pathway. Vif may also inhibit A3G through mechanisms independent of proteasomal degradation. Binding of Vif to A3G is essential for its degradation since disruption of this interaction is predicted to stimulate intracellular antiviral immunity. In this paper we will discuss the different binding partners between both proteins as one of the major challenges for the development of new antiviral drugs.

Partial Text

Vif is a 23-kDa cytoplasmic protein that is expressed from a partially spliced mRNA in Rev-dependent manner during the late phase of HIV-1 replication. The human immunodeficiency virus type 1 (HIV-1) Vif protein is essential for virus replication in primary lymphoid and myeloid cells, but is dispensable for efficient replication in several transformed T-cell lines as well as in nonlymphoid cell lines such as HeLa and 293T [1–3]. Cells that are unable to support the replication of Vif-defective HIV-1 (HIV-1∆Vif) have been termed “nonpermissive,” while cells that can sustain HIV-1∆Vif replication are termed “permissive.”

A3G belongs to a family of polynucleotide cytidine deaminases (CDAs), whose members include seven family members, named APOBEC3A to H (A3A–H). All of these genes are clustered on chromosome 22 [10, 11]. During mammalian evolution APOBEC3 (A3) family members have evolved from a single gene in mice, located on chromosome 15, to eight genes (A3A–H) in primates [10, 11]. Interestingly, expansion of the A3 gene cluster contrasts with the decline in retrotransposition activity in primates [10–12]. This observation raises the possibility that APOBEC3 genes may have evolved to prevent genomic instability caused by endogenous retroelements [13].

Expression of A3 proteins in HIV-1 infected cells can lead to their encapsidation into progeny virions through recruitment to viral or transposon capsid structures, probably involving Gag proteins and viral RNA [29, 34–37]. Deaminases will be delivered to the target cell where they will deaminate cytidines to uridines during the synthesis of the minus-strand viral cDNA [38, 39]. Consequently, during the synthesis of the plus-strand DNA, adenosines are incorporated instead of the original guanines resulting in G-to-A substitution. This process of deamination that will result in the loss of genetic integrity and protein function is commonly referred as hypermutation [40–42]. However, there is increasing evidence that A3G is able to restrict HIV-1 infection in the absence of deaminase activity [8, 43–45].

To overcome the antiviral effect of APOBEC3 proteins, in particular A3G and A3F, HIV-1 encode the Vif protein. The mode of action by which Vif counteracts A3G and A3F-mediated antiviral activity has been extensively studied. Vif neutralizes the antiviral activity of A3G and A3F by forming a RING-finger E3 ubiquitin complex with Elongin B (EloB) and C (EloC), Cullin 5 (Cul5) and Ring-box protein 2 (Rbx2) (Figure 1(a)). By bringing A3G into contact with the RING-finger E3 ubiquitin complex, Vif promotes A3G polyubiquitination and its degradation in the 26S proteasome [56–63]. A more a recent report suggested that A3G needs Vif polyubiquitination to be degraded rather than its own polyubiquitination, [64], but this is still a matter of debate. Moreover, Vif has also been reported to directly block A3G encapsidation [57, 65, 66], reduce A3G translation [60, 65], and directly inhibit the catalytic activity of A3G [45]. It is still unknown whether all these mechanisms must operate in concert to inhibit A3G action. However, independently on the mode of action, the ultimate goal of Vif is to prevent A3G encapsidation into budding HIV-1 virions.

Recent advances on the biological role of HIV-1 Vif and A3 proteins, together with progress in deciphering how Vif counteracts A3G and A3F opened new opportunities to develop anti-HIV drugs. However, understanding the mode of action of Vif and A3G alone can provide a number of attractive targets for drug development since A3G displays the most potent activity against HIV-1.

To this date, the most successful HIV-1 antiviral drugs in the market are those that target the HIV enzymes reverse transcriptase (RT) and protease (PR). Nevertheless, other strategies have proven to be highly effective such as integrase inhibitors [101–103], and entry inhibitors like T20 and Maraviroc [104].




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