Viral infectivity factor

Viral infectivity factor
HIV-1 Vif BC-box in Complex with Human ELOB and ELOC (PDB: 3DCG​).[1]
Identifiers
Symbol	Vif
Pfam	PF00559
InterPro	IPR000475
Available protein structures: Pfam   structures / ECOD   PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

Viral infectivity factor, or Vif, is an

In the absence of Vif, APOBEC3G causes hypermutation of the viral genome, rendering it dead-on-arrival at the next host cell. APOBEC3G is thus a host defence to retroviral infection which HIV-1 has overcome by the acquisition of Vif.^[5] Vif₁ is additionally able to inhibit human A3C, A3D, A3F, and A3H haplotype II,^[6] all of which can similarly be packaged and cause hypermutation in Vif-deficient HIV-1. Different surfaces on Vif₁ are used to bind A3C, A3F, and A3G.^[7]

Vif may still be able to inhibit A3 in ways independent of degradation. Vif₁ seems to reduce the amount of A3 proteins (including A3D/G/F) packaged in the virion, and to slow down the action of any A3G that does make it in.^[8]

Vif₁ was considered as a phosphoprotein and phosphorylation seemed to be required for viral infectivity.^[9][10][11] But recent studies with the use of metabolic labelling demonstrated that serine/threonine phosphorylation of Vif₁ and A3G is not required for the interaction of Vif₁ with A3G for Vif dependent degradation of A3G and the antiviral activity of A3G.^[12] However, a recent study by Raja et al has shown that Host AKT-Mediated phosphorylation of HIV-1 Vif at Thr20 stabilizes it to enhance APOBEC3G degradation and potentiate HIV-1 infectivity.^[11]

HIV-2

Vif₂ is only about ~30% identical at the amino acid level to Vif₁, a result of the evolutionary separation in different source species of the two viruses (see Subtypes of HIV). In 2014, it was discovered that Vif₂ attaches to A3G and A3F using very different residues compared to Vif₁, and that it, unlike Vif₁, cannot inhibit A3D at all.^[2] In 2016, it was found that Vif₂ also attaches to A3C differently.^[7] In 2021, it was found that Vif₂ inhibits A3B (which HIV-1 does not) and that A3B is able to inhibit a Vif-less HIV-2 (but not a Vif-less HIV-1). As A3B is also implicated in hypermutation in cancer, this discovery could lead to a way to slow down cancer cells.^[13]

As of January 2023^[update], no structure of Vif₂ can be found in the Protein Data Bank. However, it is known from the related Vif_mac (SIV_mac Vif) that it probably binds A3B in the same orientation as Vif₁ does for A3G.^[14]

Drug target

Ever since the 2000s, there has been interest in developing drugs that disarm the virus by inhibiting Vif.^[5] An 2018 review lists 17 small molecules capable of stopping viral replication by Vif inhibition, and categorized them into the functional categories of Vif multimerization targeting, A3G-Vif-targeting (two subcategories by the binding interface disrupted), Vif-EloC targeting, and A3G-upregulating. Two of the drugs were further checked for resistance potential. It turns out that the virus can become resistant in laboratory conditions after exposure to increasing amounts of either drug.^[15]

In July 2021, the Chinese