Small-molecule inhibition of HIV-1 Vif

Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
Nature Biotechnology (Impact Factor: 41.51). 10/2008; 26(10):1187-92. DOI: 10.1038/nbt.1496
Source: PubMed


The HIV-1 protein Vif, essential for in vivo viral replication, targets the human DNA-editing enzyme, APOBEC3G (A3G), which inhibits replication of retroviruses and hepatitis B virus. As Vif has no known cellular homologs, it is an attractive, yet unrealized, target for antiviral intervention. Although zinc chelation inhibits Vif and enhances viral sensitivity to A3G, this effect is unrelated to the interaction of Vif with A3G. We identify a small molecule, RN-18, that antagonizes Vif function and inhibits HIV-1 replication only in the presence of A3G. RN-18 increases cellular A3G levels in a Vif-dependent manner and increases A3G incorporation into virions without inhibiting general proteasome-mediated protein degradation. RN-18 enhances Vif degradation only in the presence of A3G, reduces viral infectivity by increasing A3G incorporation into virions and enhances cytidine deamination of the viral genome. These results demonstrate that the HIV-1 Vif-A3G axis is a valid target for developing small molecule-based new therapies for HIV infection or for enhancing innate immunity against viruses.

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    • "Nathans et al. reported 25 candidate small molecules which recover APOBEC3G expression levels in the presence of Vif by using YFP- and RFP-fused APOBEC3G protein [20]. However, none of these molecules have structural similarity to the molecules we found, likely because different libraries and/or different screening methods were used. "
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    ABSTRACT: Background HIV-1 Vif is essential for virus replication in natural target cells such as T cells and macrophages. Vif recruits a ubiquitin ligase to degrade restrictive APOBEC3 proteins. APOBEC3G is one of the most potent retroviral restriction factors targeted by Vif and, as such, the Vif-APOBEC3G interaction has emerged as a promising HIV-1 therapeutic target. Methods 20,000 small molecules were used in live-cell screens for those that preserve EGFP-APOBEC3G fluorescence and luciferase-APOBEC3G luminescence in the presence of HIV-1 Vif. Results 2 compounds with similar core structures preserved APOBEC3G levels in the presence of Vif. 10 μM of compound restored APOBEC3G to levels sufficient for incorporation into vif-proficient virus particles and restriction of virus infectivity. Vif-dependent APOBEC3G polyubiquitination and general proteasomal activity were unaffected at the same concentration. Conclusions The small molecules described here preserve APOBEC3G levels and activity in the presence of Vif. These molecules are starting points for further development as antiretrovirals.
    Full-text · Article · Jul 2014 · Virology Journal
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    • "Several small molecule inhibitors targeting the Vif-A3 axis (Cen et al., 2010; Xiao et al., 2007) have been developed, most notably is the molecule RN-18 that was shown to enhance Vif degradation, increase the abundance of A3G, A3F, and A3C leading to inhibited replication of HIV-1 in cultured cells (Nathans et al., 2008). Several other compounds protecting A3G from proteasomal degradation have also been identified (Cen et al., 2010). "
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    ABSTRACT: Human APOBEC3 (A3) proteins are host-encoded intrinsic restriction factors that inhibit the replication of many retroviral pathogens. Restriction is believed to occur as a result of the DNA cytosine deaminase activity of the A3 proteins; this activity converts cytosines into uracils in single-stranded DNA retroviral replication intermediates. A3 proteins are also equipped with deamination-independent means to restrict retroviruses that work cooperatively with deamination-dependent restriction pathways. A3 proteins substantially bolster the intrinsic immune system by providing a powerful block to the transmission of retroviral pathogens; however, most retroviruses are able to subvert this replicative restriction in their natural host. HIV-1, for instance, evades A3 proteins through the activity of its accessory protein Vif. Here, we summarize data from recent A3 structural and functional studies to provide perspectives into the interactions between cellular A3 proteins and HIV-1 macromolecules throughout the viral replication cycle.
    Preview · Article · Mar 2014 · Structure
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    • "units/virion (Nowarski et al., 2008), potentially ensuring that an adequate number of virions that do not carry A3G is produced, which can productively infect cells and sustain infection. Candidate drug molecules targeting the A3G–Vif axis either suppress Vif, upregulate A3G expression or activity, or block the interaction of Vif and A3G (Cen et al., 2010; Dapp et al., 2012; Ejima et al., 2011; Nathans et al., 2008), in each case resulting effectively in an increased fraction of budding virions incorporating A3G. Our goal therefore was to identify the minimum fraction of progeny virions that must incorporate A3G in order to render productive HIV-1 infection "
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    ABSTRACT: The contest between the host factor APOBEC3G (A3G) and the HIV-1 protein Vif presents an attractive target of intervention. The extent to which the A3G–Vif interaction must be suppressed to tilt the balance in favor of A3G remains unknown. We employed stochastic simulations and mathematical modeling of the within-host dynamics and evolution of HIV-1 to estimate the fraction of progeny virions that must incorporate A3G to render productive infection unsustainable. Using three different approaches, we found consistently that a transition from sustained infection to suppression of productive infection occurred when the latter fraction exceeded ~0.8. The transition was triggered by A3G-induced hypermutations that led to premature stop codons compromising viral production and was consistent with driving the basic reproductive number, R0, below unity. The fraction identified may serve as a quantitative guideline for strategies targeting the A3G–Vif axis.
    Full-text · Article · Jan 2014 · Virology
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