Small-Molecule Inhibition of Human Immunodeficiency Virus Type 1 Replication by Targeting the Interaction between Vif and ElonginC

Abstract

The HIV-1 viral infectivity factor (Vif) protein is essential for viral replication. Vif recruits cellular ElonginB/C-Cullin5 E3 ubiquitin ligase to target the host antiviral protein APOBEC3G (A3G) for proteasomal degradation. In the absence of Vif, A3G is packaged into budding HIV-1 virions and introduces multiple mutations in the newly synthesized minus-strand viral DNA to restrict virus replication. Thus, the A3G-Vif-E3 complex represents an attractive target for development of novel anti-HIV drugs. In this study, we identified a potent small molecular compound (VEC-5) by virtual screening and validated its anti-Vif activity through biochemical analysis. We show that VEC-5 inhibits virus replication only in A3G-positive cells. Treatment with VEC-5 increased cellular A3G levels when Vif was coexpressed and enhanced A3G incorporation into HIV-1 virions to reduce viral infectivity. Coimmunoprecipitation and computational analysis further attributed the anti-Vif activity of VEC-5 to the inhibition of Vif from direct binding to the ElonginC protein. These findings support the notion that suppressing Vif function can liberate A3G to carry out its antiviral activity and demonstrate that regulation of the Vif-ElonginC interaction is a novel target for small-molecule inhibitors of HIV-1.

Identification of an HIV-1 replication inhibitor which rescues host restriction factor APOBEC3G in Vif–APOBEC3G complex

“…(Gabuzda et al, 1992;Mariani et al, 2003;Marin et al, 2003;Mehle et al, 2004a,b;Sheehy et al, 2003;Stopak et al, 2003;Zhang et al, 2012). The key role of Vif against host defense protein APOBEC3G makes it a good target to develop new anti-HIV-1 therapeutics Cen et al, 2010;Nathans et al, 2008;Zuo et al, 2012).…”

APOBEC3F/G and Vif: Action and Counteractions

“…For instance, a zinc chelator named TPEN (N,N,N',N'-tetrakis-(2-pyridylmethyl) ethylenediamine) has been shown to specifically inhibit the Vif-Cullin 5 interaction and to inhibit Vif functions ). The Vif-Elongin C interaction can also be affected by targeting the Vif SLQ motif with a small molecule (VEC-5) (Zuo et al 2012). Interestingly, this compound does not only protect A3G but also A3C and A3F from Vif-induced Encyclopedia of AIDS DOI 10.1007/978-1-4614-9610-6_376-1 # Springer Science+Business Media New York 2015 proteasomal degradation, and it enhances A3G incorporation into the progeny virions.…”

The Road Less Traveled: HIV's Use of Alternative Routes through Cellular Pathways

“…Conventional drug design strategies which target hostvirus interactions are considered advantageous since the mutational variability of viral proteins like Vif is constrained to the binding domains of slowly evolving host cell proteins; however, we foresee a new kind of resistance whereby competent viral variants may completely reroute to bind and utilize alternative host domains or partners available within the same cellular pathway. For example, while FIV Vif, in a manner similar to that of HIV-1, contains a conserved BC-box and has similarly been shown to specifically assemble with Elongin-B/C and cullin-5 in degrading the feline APOBEC3 protein (75), a recently identified small molecule (VEC-5) which completely abolishes HIV-1 Vif binding to Elongin-C and cullin-5 did not affect FIV Vif assembly to these proteins or the consequent feline APOBEC3 degradation (79). This suggests that while the two Vif variants interact with the same cellular Elongin-B/C and cullin-5 proteins, the detailed interacting interfaces are distinct and the FIV complex may highlight a conceivably latent escape mechanism for challenged HIV-1 Vif.…”