Clade-Specific Alterations within the HIV-1 Capsid Protein with Implications for Nuclear Translocation

Abstract

The HIV-1 capsid (CA) protein has emerged as an attractive therapeutic target. However, all inhibitor designs and structural analyses for this essential HIV-1 protein have focused on the clade B HIV-1 (NL4-3) variant. This study creates, overproduces, purifies, and characterizes the CA proteins from clade A1, A2, B, C, and D isolates. These new CA constructs represent novel reagents that can be used in future CA-targeted inhibitor design and to investigate CA proteins’ structural and biochemical properties from genetically diverse HIV-1 subtypes. Moreover, we used surface plasmon resonance (SPR) spectrometry and computational modeling to examine inter-clade differences in CA assembly and binding of PF-74, CPSF-6, and NUP-153. Interestingly, we found that HIV-1 CA from clade A1 does not bind to NUP-153, suggesting that the import of CA core structures through the nuclear pore complex may be altered for viruses from this clade. Overall, we have demonstrated that in silico generated models of the HIV-1 CA protein from clades other than the prototypically used clade B have utility in understanding and predicting biology and antiviral drug design and mechanism of action.