Basic Science Award

We have previously shown that infection-impaired HIV with incompletely processed capsid-spacer protein 1 (CA-SP1) is rescued by either cellular activation or increased expression of HSP90AB1, a member of the cytosolic heat shock protein 90 family of cellular chaperones. Expanding on our initial results, we found that HSP90AB1 is present in HIV virions and that recombinant HSP90AB1, but not nonfunctional mutated HSP90AB1E42A+D88A, restores infectivity to HIV with mutations in CA that alter core stability and impair infectivity. Similar to what we previously reported for HIV with incompletely processed CA-SP1, the CA mutants were hypersensitive to pharmacological inhibition of HSP90AB1. In agreement with a recent report (Roesch, et al. PLoS Pathog, e1002792, 2012), we found that culturing HIV at 39.5 °C enhanced viral infectivity up to 30-fold in human peripheral blood mononuclear cells (p = 0.002) and rescued CA-mutant infectivity in nonactivated cells, concurrent with elevated expression of HSP90AB1 during hyperthermia. In sum, the transdominant effect of HSP90AB1 on CA-mutant HIV infectivity suggests a potential role for this class of cellular chaperones in wild-type HIV infection. In this proposal, we aim to investigate the profile of HSP90AB1 incorporation among retroviruses and to identify the postentry stage of HIV infection that is regulated by HSP90AB1 expression. The experimental design includes detection of HSP90AB1 in multiple retroviruses generated from different primary human cells. In addition, we will determine the influence of HSP90AB1 on HIV uncoating and reverse transcription. The results from these studies are expected to define a functional interaction between HSP90AB1 and postentry HIV infection and thus might ultimately lead to novel targets for therapeutic intervention.