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

Abstract

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 heterologous DCCR5 hematopoietic stem cell transplantation, 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 hsp90 is required for HIV-1 reactivation mediated by the T-cell receptor, phorbol esters, TNF-a, inhibition of FOXO-1, and agonists of TLR-7 and TLR-8. Inhibition of hsp90 abrogated activation of the NF-kB, NFAT and AP-1 signal transduction pathways, and this phenotype was recapitulated by targeting TAK1, an hsp90 client protein. Within the CD4+ T cell population, naive and 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.