Activation of HIV Transcription with Short-Course Vorinostat in HIV-Infected Patients on Suppressive Antiretroviral Therapy

Abstract

Human immunodeficiency virus (HIV) persistence in latently infected resting memory CD4+ T-cells is the major barrier to HIV cure. Cellular histone deacetylases (HDACs) are important in maintaining HIV latency and histone deacetylase inhibitors (HDACi) may reverse latency by activating HIV transcription from latently infected CD4+ T-cells. We performed a single arm, open label, proof-of-concept study in which vorinostat, a pan-HDACi, was administered 400 mg orally once daily for 14 days to 20 HIV-infected individuals on suppressive antiretroviral therapy (ART). The primary endpoint was change in cell associated unspliced (CA-US) HIV RNA in total CD4+ T-cells from blood at day 14. The study is registered at ClinicalTrials.gov (NCT01365065). Vorinostat was safe and well tolerated and there were no dose modifications or study drug discontinuations. CA-US HIV RNA in blood increased significantly in 18/20 patients (90%) with a median fold change from baseline to peak value of 7.4 (IQR 3.4, 9.1). CA-US RNA was significantly elevated 8 hours post drug and remained elevated 70 days after last dose. Significant early changes in expression of genes associated with chromatin remodeling and activation of HIV transcription correlated with the magnitude of increased CA-US HIV RNA. There were no statistically significant changes in plasma HIV RNA, concentration of HIV DNA, integrated DNA, inducible virus in CD4+ T-cells or markers of T-cell activation. Vorinostat induced a significant and sustained increase in HIV transcription from latency in the majority of HIV-infected patients. However, additional interventions will be needed to efficiently induce virus production and ultimately eliminate latently infected cells.Trial RegistrationClinicalTrials.gov NCT01365065

Relationship between Measures of HIV Reactivation and Decline of the Latent Reservoir under Latency-Reversing Agents

“…Here, we deal with the issue of how we estimate the increase in the HIV reactivation rate based on the current number of latently infected cells with reactivated HIV transcription. The increase in this number during LRA treatment is in practice measured indirectly, most often by the increase in CA US HIV RNA (14,(18)(19)(20). We show that the number of reactivated latent cells depends not only on the frequency in time at which the cells reactivate transcription, but also on the cell life span in the HIV-transcribing state.…”

“…Although all investigated LRAs showed increased virus transcription, no changes in the latent-reservoir size were detected after the use of LRA in vivo (14,(18)(19)(20) or in vitro (24). One reason could be the short time during which LRAs were given to ART patients (ranging from 8 weeks for panobinostat to 3 weeks for romidepsin and 3 days for disulfiram), making the detection of reservoir decay problematic.…”

“…Various latencyreversing agents (LRAs) have been investigated, including drugs that trigger the NF-B activation pathway, such as prostratin (10) and bryostatin (11) analogues; BET inhibitors enhancing the binding of the viral Tat protein to the HIV TAR element (12); disulfiram (13,14); and histone deacetylase inhibitors (HDACi), like valproic acid (15,16), vorinostat (17,18), panobinostat (19), and romidepsin (20), that act as epigenetic modifiers. The HDACi were the first compounds to enter clinical trials, given the extensive data on their toxicity from studies in individuals with malignancy.…”

“…The HDACi were the first compounds to enter clinical trials, given the extensive data on their toxicity from studies in individuals with malignancy. However, all clinical trials of HDACi have demonstrated no decline in the frequency of latently infected cells (15,(18)(19)(20).…”

“…Changes in HIV transcription have been demonstrated in all trials by showing an increase in the level of cell-associated HIV RNA (CA RNA) in total and resting CD4 ϩ T cells (21). Synthesis of unspliced (US) HIV RNA is the first step in virus transcription, and multiple subsequent steps, including splicing, cytoplasmic export, synthesis of the regulatory proteins tat and rev, maturation, and budding, are subsequently required for virion release (22), but US HIV RNA is a marker that HIV transcription has been initiated (18).…”