Human immunodeficiency virus 1 group-specific antigen polyprotein (Gag)

The Human immunodeficiency virus 1 group-specific antigen polyprotein (Gag) is the primary structural precursor required for the assembly of HIV-1 particles (UniProt P03367). Synthesized as a 55 kDa polyprotein (Pr55Gag), it coordinates the packaging of the viral genome and the budding of new virions from the host cell plasma membrane (PubMed: 22440128). Following budding, Gag undergoes sequential cleavage by the viral protease into distinct proteins: matrix (MA/p17), capsid (CA/p24), nucleocapsid (NC/p7), and p6, which are essential for viral infectivity (NIH). This maturation process is a key target for antiretroviral drugs, such as maturation inhibitors that prevent the final cleavage step between the capsid and spacer peptide 1 (SP1). Additionally, the capsid subunit of Gag is the target for novel long-acting inhibitors like Lenacapavir, which disrupt multiple stages of the viral life cycle including nuclear entry and capsid assembly (PubMed: 32612214). Understanding Gag's structural transitions is vital for overcoming drug resistance, which often arises from mutations within the Gag cleavage sites or the CA domain. As a central player in viral morphogenesis, Gag remains a high-priority target for the development of next-generation HIV therapies.

Other names

Pr55GagGag polyproteinp55HIV-1 Gag

Maturation inhibitors bind to the Gag polyprotein at the CA-SP1 junction to prevent proteolytic cleavage, while capsid inhibitors bind to the CA domain of Gag to disrupt assembly and nuclear entry.