William J Hey-Cunningham, Kirby Institute, University of New South Wales Medicine, University of New South Wales, Australia
Kersten K Koelsch, Kirby Institute, University of New South Wales Medicine, University of New South Wales, Australia
Giuseppe Pantaleo, Division of Immunology and Allergy, Lausanne University Hospital, Lausanne, Switzerland
Kim Krogsgaard, Bionor Pharma ASA, Oslo, Norway, Norway
Maja Sommerfelt, Bionor Pharma ASA, Oslo, Norway, Norway
Remi Fromentin, Centre de Recherche du CHUM, Montreal, Quebec, Canada, Canada
Nicolas Chomont, Centre de Recherche du CHUM, Montreal, Quebec, Canada, Department of Microbiology, Infectiology, and Immunology, Université de Montréal, Faculty of Medicine, Montreal, Quebec, Canada, Canada
Pharmacologically-induced activation of replication competent proviruses from latency inthe presence of antiretroviral treatment (ART) has been proposed as a step towards curingHIV-1 infection. However, until now, approaches to reverse HIV-1 latency in humans haveyielded mixed results. Here, we report a proof-of-concept phase Ib/IIa trial where 6 aviremicHIV-1 infected adults received intravenous 5 mg/m2 romidepsin (Celgene) once weekly for3 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-1RNA 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 quantifi-able 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, romidepsinsafely 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.