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

Abstract

An estimated 39.9 million people live with HIV-1 globally. While combined antiretroviral therapy has significantly reduce the mortality rate of HIV-1 patients by controlling the virus and preventing its spreading, interrupting the treatment causes the virus to rebound from a latent reservoir that is mostly present in memory CD4+ T cells. Therefore, treatment is not curative but rather lifelong. Alternative treatment strategies involve the use of pharmacological agents to Induce deep latency or stimulation of latently infected cells to facilitate immune-mediated clearance. The multifactorial nature of HIV-1 latency is associated with the infected CD4+ T cell's activation status. Hence to perturb latency, it is necessary to target several pathways simultaneously without compromising CD4+ T cell activity and function. HIV-1 latency has been demonstrated to be regulated by Hsp90, although knowledge on the pathways is limited. However, Hsp90 known to enhance the proper folding of numerous cellular proteins required for HIV-1 gene expression, for this reason, 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. Here we showed that Hsp90 is necessary for HIV-1 reactivation in the Jurkat model, which is mediated via the T-cell receptor, agonists of TLR-7 and TLR-8, phorbol esters, TNF-α, and FOXO-1 suppression. Additionally, in primary cells, targeting Hsp90 reduced HIV-1 gene expression induced by stimulation the TCR or in the presence of IL7/IL15 or a FOXO-1 inhibitor. The activation of the NF-kB, NFAT, and AP-1 signal transduction pathways was inhibited by chemically inhibiting Hsp90. We showed that Hsp90 inhibition for HIV-1 was mostly significant within the CD4+ T cell population, CDRA45+ CCR7+ “naïve” and CD45RA- CCR7- “effector memory” 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.