Romidepsin Promising HDAC Inhibitor for Reversing HIV Latency

Viral induction greater than any other latency reversing agent.

In order for HIV to be cured, there needs to be removal of latent virus from reservoirs in immune cells throughout the body.

HIV latency depends on the activity of proteins from the human host called histone deacetylases (HDAC), and prior research has shown that HDAC inhibitors (HDACi) can disrupt HIV latency. A recent clinical trial of an HDACi that has shown potential in preclinical studies answers some questions about the drug’s potential to eliminate HIV from the body.

The trial was designed to further investigate the potential of HDACi as the latency reversal component in the “kick and kill approach” to purge HIV reservoirs. Researchers chose an HDACi called romidepsin and investigated its safety and potential for reversing HIV latency in individuals who had undergone long-term antiretroviral therapy (ART), as well as its impact on T cells.

The trial studied 6 white participants with a median age of 56 and a median time on ART of 10 years. Participants received 1 romidepsin infusion per week for 3 weeks and were followed for several more weeks thereafter. All individuals suffered side effects, but these were manageable and all participants completed treatment.

When researchers analyzed participants’ blood at different intervals during the trial, they found the exact biochemical response to HDAC inhibition that they expected. They also observed evidence of HIV transcription — the first step of latency reversal – in all participants.

After the second infusion, HIV RNA became detectable and quantifiable with standard clinical assays in blood plasma in 5 of the 6 participants. The researchers stated that “this establishes a new benchmark for future trials investigating the in vivo potency of latency reversing agents to be used in HIV eradication efforts.”

Moreover, romidepsin did not alter the proportion of HIV-specific T cells, inhibit T-cell cytokine production, or induce other changes that suggest an impaired T cell response. According to the researchers, this is “critically important for future trials combining HDACi with interventions designed to enhance killing of latently infected cells by cytotoxic T cells.”

“The present study demonstrated potent in vivo latency reversal with a single drug resulting in increased plasma HIV-1 RNA that was readily quantified with standard commercial assays and did not show negative effects on T cell immunity,” the study authors wrote.

Moreover, “the magnitude of viral induction in the present study was greater than anything previously reported for any latency reversing agent tested in humans.”

The researchers acknowledge that, as in previous studies, their findings do not answer the question of what proportion out of the total pool of inducible latently infected cells were “kicked out of” latency in the participants and that “despite the increases in viral production and preserved T cell functions, no substantial changes in the size of the HIV reservoir were observed.”

However, researchers feel that their findings have important implications for the use of romidepsin as the latency reversal agent in a multi-component HIV eradication strategy where this drug may be combined with interventions designed to enhance killing of latently infected cells.