Heat shock protein 90 is a chaperone regulator of HIV-1 latency

An estimated 32 million people live with HIV-1 globally. Combined antiretroviral therapy suppresses viral replication but therapy interruption results in viral rebound from a latent reservoir mainly found in memory CD4+ T cells. Treatment is therefore lifelong and not curative. Eradication of this viral reservoir requires hematopoietic stem cell transplantation from hemizygous or homozygous ΔCCR5 donors, which is not broadly applicable. Alternative cure strategies include the pharmacological reactivation of latently infected cells to promote their immune-mediated clearance, or the induction of deep latency. HIV-1 latency is multifactorial and linked to the activation status of the infected CD4+ T cell. Hence to perturb latency, multiple pathways need to be simultaneously targeted without affecting CD4+ T cell function. Hsp90 has been shown to regulate HIV-1 latency, although knowledge on the pathways is limited. Because Hsp90 promotes the proper folding of numerous cellular proteins required for HIV-1 gene expression, we hypothesized that Hsp90 might be a master regulator of latency. We tested this hypothesis using a polyclonal Jurkat cell model of latency and ex-vivo latently infected primary CD4+ T cells. We found that, in the Jurkat model, Hsp90 is required for HIV-1 reactivation mediated by the T-cell receptor, phorbol esters, TNF-α, inhibition of FOXO-1, and agonists of TLR-7 and TLR-8. In primary cells, Hsp90 regulates HIV-1 gene expression induced by stimulation of the T-cell receptor or in the presence of IL-7/IL-15 or a FOXO-1 inhibitor. Chemical inhibition of Hsp90 abrogated activation of the NF-kB, NFAT and AP-1 signal transduction pathways. Within the CD4+ T cell population, CDRA45+ CCR7+ "naïve" and CD45RA- CCR7- "effector memory" cells were most sensitive to Hsp90 inhibition, which did not perturb their phenotype or activation state. Our results indicate that Hsp90 is a master regulator of HIV-1 latency that can potentially be targeted in cure strategies.