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.Trial Registrationclinicaltrials.gov NTC02092116

No abstract

Toll-like receptor (TLR) agonists are potent enhancers of innate antiviral immunity and may also reverse HIV-1 latency. Therefore, TLR agonists have a potential role in the context of a "shock-and-kill" approach to eradicate HIV-1. Our extensive preclinical evaluation suggests that a novel TLR9 agonist, MGN1703, may indeed perform both functions in an HIV-1 eradication trial. Over the past decade, the importance of NK cells in controlling human immunodeficiency virus type 1 (HIV-1) infection in vivo has become increasingly clearer (1-3). In response, novel approaches to induce NK cell-directed enhancement of immune function are being developed (4). One approach to improving NK cell function is via Toll-like receptor 9 (TLR9) activation.TLR9 ligands stimulate potent antiviral responses via an activation pathway initiated by the TLR9 recognition of nonmethylated cytosine-guanine dinucleotide (CG) motifs found in bacterial, viral, and mitochondrial DNAs (5). This pathway is initiated by pattern recognition in plasmacytoid dendritic cells (pDCs) and B cells, as these cells exhibit high levels of TLR9 expression. Following TLR9 engagement, type I interferon (primarily interferon alpha [IFN-␣]) is produced and secreted by pDCs. IFN-␣ activates NK cells as well as the promoters of interferon-stimulated genes (e.g., CXCL-10), resulting in a targeted antiviral inflammatory environment. T and NK cells within this local environment become further activated (e.g., upregulated CD69 surface expression on NK and T cells and altered expression of NK cell receptors) (6). The overall function of activated T and NK cells is to clear the pathogen that initiated the cascade in the TLR9-expressing cells.