Researchers give insight into the role of host-cell protein CypA in HIV infectivity
A deeper understanding of the host factor's function may lead to promising new ways to target HIV
A collaborative research team from the USA have investigated the interactions between HIV and the host-cell protein cyclophilin A (CypA), shedding light on how this protein regulates HIV-1 infectivity.
In humans, the protein CypA can either promote or inhibit infection through direct interactions with the HIV-1 capsid (CA). In order to provide an insight into how this works, using magic-angle spinning NMR and molecular dynamics, the group, which was led by Tatyana Polenova (University of Delaware, USA), examined the role of conformational dynamics in HIV-1 CA assemblies in the escape from CypA dependence.
Through analysis of wild-type and the A92E and G94D CypA escape mutants, it was revealed that assembled CA is dynamic, particularly in loop regions. The CypA loop in assembled wild-type CA from two strains was found to exhibit unprecedented mobility on the nanosecond to microsecond timescales, and the experimental NMR dipolar order parameters were discovered to be in quantitative agreement with those calculated from MD trajectories. These findings suggested that CA escapes from CypA dependence through dynamic allostery. With this in mind, the team concluded that the host factor's function in HIV infectivity may not be primarily associated with a structural change of the capsid core, but with altering its dynamics, such as the reduction of motions for the CypA loop.
"It is the first time that quantitative agreement between experiment and computation was achieved in a dynamics study, and it's particularly exciting that this was attained for such a complex system," Polenova commented. "We hope this work may guide the development of new therapeutic interventions, such as small molecules that would serve as interactors with the HIV capsid and inhibit these dynamics."