Human immunodeficiency virus 1 Gag polyprotein (Gag) (Gag)

The Human immunodeficiency virus 1 Gag polyprotein (Gag) is the primary structural protein responsible for the assembly and release of HIV-1 particles (UniProt: P04591). It is synthesized as a 55 kDa precursor (Pr55Gag) that migrates to the host cell plasma membrane, where it coordinates the packaging of the viral RNA genome and the recruitment of the Gag-Pol polyprotein (PubMed: 12151037). During or shortly after viral budding, the viral protease cleaves Gag into four major domains—Matrix (MA), Capsid (CA), Nucleocapsid (NC), and p6—plus two spacer peptides, SP1 and SP2 (StatPearls: NBK556033). This proteolytic processing, termed maturation, is a prerequisite for viral infectivity, as it allows for the formation of the conical capsid core. Pharmacological targeting of Gag has yielded two major classes of inhibitors: capsid inhibitors (e.g., Lenacapavir), which interfere with CA-mediated assembly and nuclear import, and maturation inhibitors (e.g., Bevirimat), which prevent the final cleavage between CA and SP1 (PubMed: 33168600). Gag is an attractive therapeutic target because it is essential for multiple stages of the viral life cycle and possesses conserved regions that can be exploited to treat multi-drug resistant HIV-1 infections (NIH: ClinicalInfo). Despite its potential, the development of resistance mutations remains a significant therapeutic challenge in Gag-targeted drug design.

Other names

Pr55Gagp55Group-specific antigenHIV-1 GagGag polyprotein

Capsid inhibition (interference with CA assembly, disassembly, and nuclear transport) and maturation inhibition (blocking the proteolytic cleavage of the CA-SP1 junction)