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The mysterious Vif protein: How does it contribute to the spread and evolution of HIV?
In the global health issue of HIV, Viral infectivity factor (Vif for short) is a striking supporting role. This accessory protein plays an important role in HIV and other lentiviruses, and its main task is to interfere with the antiviral activity of the human enzyme APOBEC. Specifically, Vif promotes the ubiquitination and cellular degradation of enzymes such as APOBEC3G (referred to as A3G), thereby allowing the virus to multiply in the human body. APOBEC is a cellular cytidine deaminase that can mutate viral nucleic acids, causing the virus to be unable to survive in the next host.
In the absence of Vif, APOBEC3G will hypermute the viral genome, causing it to "die on arrival in the next host."
Vif’s mechanism
Vif in HIV-1
Vif in HIV-1 (called Vif1) is a 23-kilodalton protein that is essential for viral replication. It works by marking APOBEC3G as a target for proteasomal degradation, preventing it from entering the virus upon budding from the host cell. Vif1 can fuse with A3G and the Cullin5 E3 ubiquitin ligase in cells, and bind to the CBFB co-factor, thereby degrading the A3G mark.
Vif1 is now recognized as a phosphorylated protein, and this phosphorylation appears to be an important requirement for viral infectivity.
Recent studies have shown that AKT-mediated phosphorylation of HIV-1 Vif also plays a crucial role in the stability and degradation of APOBEC3G and further enhances HIV-1 infectivity.
Vif in HIV-2
Compared with HIV-1, HIV-2's Vif (called Vif2) is only about 30% similar at the amino acid level. Recently, it was discovered that Vif2 uses different amino acid residues to bind to A3G and A3F, but its ability to inhibit A3D is completely lacking. This shows that HIV-2 has different adaptive strategies from HIV-1 during its evolution.
Vif2 was found to be able to inhibit A3B in 2021, but A3B has an auxiliary inhibitory effect on HIV-2 lacking Vif.
Vif as a drug target
Since the 2000s, researchers have sought to develop drugs that could disarm the virus by inhibiting Vif. A 2018 review listed 17 small molecule drugs that can stop viral replication through Vif inhibition. These drugs are divided into several functional categories, including Vif aggregate targeting and A3G-Vif targeting, among others.
After being treated with gradually increasing doses of some drugs under laboratory conditions, the virus showed a certain degree of drug resistance.
In July 2021, China's National Medical Products Administration provided conditional approval for azvudine, a drug claimed to simultaneously inhibit HIV-1 Vif and act as a nucleoside reverse transcriptase inhibitor.
Vif in other species
In addition to human immunodeficiency virus, Vif is also found in other lentiviruses, such as simian immunodeficiency virus (SIV), feline immunodeficiency virus (FIV), Visna virus, and goat arthroencephalitis virus. The mammalian APOBEC3 enzyme is engaged in an evolutionary "arms race" with Vif in these viruses, constantly evolving and diversifying to escape the fate of inactivation.
Most Vifs use CBFB and CRL complexes as cofactors, but Visna-maedi viruses use CYPA instead.
The reality of this interaction gives us a deeper understanding of the evolution and changing biological mechanisms of viruses. In the fight against HIV, how can scientists harness these important mechanisms to find effective treatments?
