Heat shock protein 90 is a master regulator of HIV-1 latency
Authors: Noorsaeed Somaya , AlBurtamani Nawal , Rokan Ahmed , Fassati Ariberto 
Published: August 2024

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 ΔCCR5 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-α, 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, naïve 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.

Author summary

HIV-1 affects around 32 million people globally. Current treatments, known as combined antiretroviral therapy, can suppress the virus but do not cure the infection and if the treatment stops, the virus comes back. This happens because the virus hides in a population of immune cells called memory CD4+ T cells. To truly cure HIV-1, some strategies involve complex and risky procedures like hematopoietic stem cell transplants, which are not widely applicable. Another approach is to reactivate the hidden virus in the cells, so the immune system can eliminate it, or to force the virus into an even deeper hiding state. HIV-1 latency, or its ability to hide in cells, is influenced by many factors and cells need to be activated to disrupt it. Hsp90 is a chaperone that regulates the function of numerous proteins important for HIV-1 latency and is known to play a role in maintaining this hidden state of the virus. We therefore wondered if Hsp90 acts like a master regulator of latency. Using lab-based models, we discovered that Hsp90 is crucial for the reactivation of HIV-1 through various pathways. By inhibiting Hsp90, the activation of key signalling pathways necessary for viral reactivation was blocked. Importantly, blocking Hsp90 did not harm the CD4+ T cells’ function or state. Hsp90 inhibitors, already tested in cancer treatments, could thus be a promising avenue for HIV-1 cure strategies, as they seem to hold the key to maintaining HIV-1 latency.