Maturation inhibitors facilitate virus assembly and release of HIV-1 capsid P224 mutant

• Published in: Virology (New York, N.Y.) N.Y.), 2018-08, Vol.521, p.44-50
• Main Authors: Timilsina, Uddhav, Ghimire, Dibya, Adhikari, Laxmi Prasad, Bhattarai, Abhi, Mishra, Nawneet, Rai, Madhu, Dubey, Ravi Chandra, Gaur, Ritu
• Format: Article
• Language: English
• Subjects: Gag assembly; HIV; Maturation inhibitors
• ISSN: 0042-6822; 1096-0341
• DOI: 10.1016/j.virol.2018.05.024

HIV-1 Maturation inhibitors (MIs) bind to the C-terminal domain of capsid protein (CA-CTD) and spacer peptide 1 (SP1) in HIV-1 Gag and inhibit the CA-SP1 cleavage by stabilizing the immature Gag. The β-turn motif, GVGGP in the HIV CA-CTD (residues 220–224) is one of the key determinants of HIV Gag assembly. In the present study, we mutated each residue of HIV-1 β-turn motif to alanine and observed complete inhibition of virus release of all mutants. This defect in virus release was rescued in the presence of maturation inhibitors; BVM and PF-46396 for P224A mutant. To our knowledge, this is the first report of identification of BVM and PF-46396-dependent capsid mutant. Our results highlight the importance of the core β-turn motif residues in immature virus assembly and suggest that the presence of MIs enhances Gag membrane binding and multimerization thereby restoring virus release of HIV Gag P224 mutant. •Mutations in the HIV-1 CA-CTD β-turn motif GVGGP inhibited virus release.•Presence of maturation inhibitors rescued virus release, infectivity and replication potential of HIV-1 CA: P224A mutant.•Increased Gag Membrane binding and multimerisation of CA: P224A mutant was observed in the presence of PF-46396.•Identified HIV-1 CA: P224A as a unique viral mutant which exhibited dependency on both classes of MIs.