Pharmacologically-induced activation of replication competent proviruses from latency in the presence of antiretroviral treatment (ART) has been proposed as a step towards curing HIV-1 infection. However, until now, approaches to reverse HIV-1 latency in humans have yielded mixed results. Here, we report a proof-of-concept phase Ib/IIa trial where 6 aviremic HIV-1 infected adults received intravenous 5 mg/m² romidepsin (Celgene) once weekly for 3 weeks while maintaining ART. Lymphocyte histone H3 acetylation, a cellular measure of the pharmacodynamic response to romidepsin, increased rapidly (maximum fold range: 3.7–7.7 relative to baseline) within the first hours following each romidepsin administration. Concurrently, HIV-1 transcription quantified as copies of cell-associated un-spliced HIV-1 RNA increased significantly from baseline during treatment (range of fold-increase: 2.4–5.0; p = 0.03). Plasma HIV-1 RNA increased from <20 copies/mL at baseline to readily quantifiable levels at multiple post-infusion time-points in 5 of 6 patients (range 46–103 copies/mL following the second infusion, p = 0.04). Importantly, romidepsin did not decrease the number of HIV-specific T cells or inhibit T cell cytokine production. Adverse events (all grade 1–2) were consistent with the known side effects of romidepsin. In conclusion, romidepsin safely induced HIV-1 transcription resulting in plasma HIV-1 RNA that was readily detected with standard commercial assays demonstrating that significant reversal of HIV-1 latency in vivo is possible without blunting T cell-mediated immune responses. These finding have major implications for future trials aiming to eradicate the HIV-1 reservoir. clinicaltrials.gov NTC02092116 One proposed way of curing HIV is to activate virus transcription and kill latently infected cells while the presence of antiretroviral therapy prevents spreading the infection. Induction of global T cell activation by mitogenic or other potent activators effectively reverses HIV-1 from latency ex vivo, but such compounds are generally too toxic for clinical use. Therefore, investigating the capacity of small molecule latency reversing agents to induce production of virus without causing global T cell activation has been a top research priority for scientists in recent years. In the present clinical trial, we demonstrate that significant viral reactivation can be safely induced using the depsipeptide romidepsin (HDAC inhibitor) in long-term suppressed HIV-1 individuals on antiretroviral therapy. Following each romidepsin infusion, we observed clear increases in lymphocyte H3 acetylation, HIV-1 transcription, and plasma HIV-1 RNA. Importantly, this reversal of HIV-1 latency could be measured using standard clinical assays for detection of plasma HIV-1 RNA. Furthermore, romidepsin did not alter the proportion of HIV-specific T cells or inhibit T cell cytokine production which is critically important for future trials combining HDAC inhibitors with interventions (e.g. therapeutic HIV-1 vaccination) designed to enhance killing of latently infected cells.

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. ClinicalTrials.gov NCT01365065 The major barrier to curing HIV is the long term persistence of latently infected resting memory T-cells in HIV-infected patients on antiretroviral therapy (ART). One strategy being pursued to eliminate latently infected cells is to activate HIV production from latently infected cells with the aim of killing latently infected cells via virus induced cell death or stimulation of an HIV-specific immune response. Histone deacetylases (HDACs) are important in maintaining HIV latency. Vorinostat, an inhibitor of HDACs (HDACi) licensed for the treatment of some malignancies, has been shown in laboratory studies and a clinical study of selected individuals to disrupt HIV latency. We examined the ability of standard dose vorinostat given daily for 14 days to activate latent HIV infection in unselected HIV-infected individuals on ART. The study showed evidence of activation of latent HIV infection in 18/20 (90%) of individuals and was safe and generally well tolerated. There were significant early changes in host gene expression, which persisted during and after the period of vorinostat. No changes were seen in immune activation or number of latently infected cells. Vorinostat was able to activate latent HIV infection in most individuals. Additional interventions will be needed to eliminate latent HIV infection.

Passive immunization with HIV-1–neutralizing monoclonal antibodies (mAbs) is being considered for prevention and treatment of HIV-1 infection. As therapeutic agents, mAbs could be used to suppress active virus replication, maintain suppression induced by antiretroviral therapy (ART), and/or decrease the size of the persistent virus reservoir. We assessed the impact of VRC01, a potent human mAb targeting the HIV-1 CD4 binding site, on ART-treated and untreated HIV-1–infected subjects. Among six ART-treated individuals with undetectable plasma viremia, two infusions of VRC01 did not reduce the peripheral blood cell–associated virus reservoir measured 4 weeks after the second infusion. In contrast, six of eight ART-untreated, viremic subjects infused with a single dose of VRC01 experienced a 1.1 to 1.8 log₁₀ reduction in plasma viremia. The two subjects with minimal responses to VRC01 were found to have predominantly VRC01-resistant virus before treatment. Notably, two subjects with plasma virus load <1000 copies/ml demonstrated virus suppression to undetectable levels for over 20 days until VRC01 levels declined. Among the remaining four subjects with baseline virus loads between 3000 and 30,000 copies, viremia was only partially suppressed by mAb infusion, and we observed strong selection pressure for the outgrowth of less neutralization-sensitive viruses. In summary, a single infusion of mAb VRC01 significantly decreased plasma viremia and preferentially suppressed neutralization-sensitive virus strains. These data demonstrate the virological effect of this neutralizing antibody and highlight the need for combination strategies to maintain virus suppression.