Identification of Novel Determinants of HIV-1 Uncoating in the Capsid Protein
Uncoating of the viral core following penetration into the target cell represents a fundamentally obscure step in the HIV-1 life cycle. Our laboratory has previously reported that mutations in the CA protein that positively and negatively alter the stability of the viral capsid shell result in impaired HIV-1 infectivity, suggesting that the HIV-1 core is optimally balanced for proper uncoating in target cells. To identify additional determinants contributing to optimal HIV-1 capsid stability in CA, I identified second-site suppressors of HIV-1 uncoating mutants by serial passage. My results indicate that CA determinants outside the CypA-binding loop can modulate the dependence of HIV-1 infection on CypA. Further, based on the recently reported full-length HIV-1 hexamer structure, my data provide novel genetic evidence of HIV-1 CA direct intersubunit interactions. My results also suggest that cellular factors are involved in HIV-1 uncoating. A detailed understanding of the mechanism and determinants of HIV-1 uncoating should facilitate the development of novel antiviral therapies targeting this key step in HIV-1 infection.