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

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 Glade B HIV-1 (NL4-3) variant. This study creates, overproduces, purifies, and characterizes the CA proteins from Glade 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-Glade differences in CA assembly and binding of PF-74, CPSF-6, and NUP-153. Interestingly, we found that HIV-1 CA from Glade Al 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 Glade. Overall, we have demonstrated that in silico generated models of the HIV-1 CA protein from clades other than the prototypically used Glade B have utility in understanding and predicting biology and antiviral drug design and mechanism of action.

Automated summary

This study isolated and characterized CA proteins from different HIV-1 subtypes and compared their assembly and inhibitor binding properties. It was found that HIV-1 CA from Glade Al showed altered interactions with NUP-153, which may affect the nuclear import of CA core structures. The in silico generated models of non-B HIV-1 CA protein were also shown to be useful for understanding and predicting the biology and mechanism of action of antiviral drugs.