- Category: Search for a Cure
- Published on Tuesday, 22 July 2014 00:00
- Written by Liz Highleyman
The HDAC inhibitor romidepsin was able to awaken latent HIV in resting T-cells, causing it to start producing new virus, but this was not associated with a decrease in the size of the viral reservoir in T-cells, researchers reported at the 20th International AIDS Conference this week in Melbourne. This finding suggests that kicking HIV out of hiding will not be adequate for a functional cure without strengthening immune response against the virus.
One approach widely used in HIV cure research is known as "kick and kill" or "shock and kill." This strategy involves using various agents to reactivate latent proviral DNA in resting cells. Once the cells are "woken up," this hidden viral genetic blueprint starts churning out new virus. This makes the virus-producing cells visible to the immune system and the escaping virus is susceptible to antiretroviral therapy (ART).
One type of agent used to kick-start resting cells are histone deacetylase or HDAC inhibitors. HDACs are enzymes that keep DNA tightly coiled in a cell's nucleus, so it cannot be used to direct production of new proteins. HDAC inhibitors reverse this process, allowing proviral DNA gene expression and production of new virus.
Ole Schmeltz Søgaard from Aarhus University Hospital in Denmark and colleagues evaluated the HDAC inhibitor romidepsin, an anticancer drug used to treat lymphoma. Previous laboratory studies showed that romidepsin is a potent activator of resting T-cells in vitro. Søgaard's team tested the safety and efficacy of the approach in people with HIV.
The study included 6 HIV positive adults (5 men and 1 woman) with a median age of 54 years. They had been on combination ART for a median of 9.5 years, but none had started during acute or primary infection. They had undetectable viral load (HIV RNA <50 copies/mL) for at least 1 year and a median CD4 count of 760 cells/mm3. People with significant cardiac disease or hepatitis B or C coinfection were excluded.
All participants in this non-randomized intervention trial received 3 once-weekly infusions of romidepsin (5 mg/m2) at days 0, 7 and 14. Follow-up continued for 21 days.
- Romidepsin increased histone H3 acetylation in lymphocytes, with the magnitude of the effect increasing after each successive dose; the effect diminished slowly and some activity was still apparent through the end of follow-up.
- Levels of cell-associated HIV RNA in CD4 T-cells rose significantly in all patients after romidepsin administration, with larger increases seen after the second and third doses compared with the first dose (mean 3.5-fold increase).
- Plasma HIV RNA also increased, reaching quantifiable levels in 5 of the 6 participants using a standard clinical viral load assay.
- The greatest activation was observed in the central memory and "term diff" T-cell subsets.
- Romidepsin rapidly altered CD4 and CD8 cell composition, with a shift towards more naive cells and fewer effector and central memory cells.
- Expression of PD1, a marker of cell exhaustion, decreased in both CD4 and CD8 cells.
- Romidepsin was generally safe and well-tolerated.
- Participants reported 36 adverse events considered related to the study drug, most of which were mild and resolved spontaneously.
- The most common side-effects were nausea (12 events), other gastrointestinal symptoms (8 events), and fatigue (5 events).
Together, these findings indicate that romidepsin acts as a reactivating agent that "kicks" latently infected cells out of latency, the researchers concluded.
Yet despite evidence of increased T-cell activation and renewed HIV replication, the size of the viral reservoir, as indicated by total HIV DNA in CD4 T-cells, did not change. Some patients experienced a small increase and others saw a decrease -- including one with an 80% reduction -- but the overall change was not significant.
"Romidepsin safely activated latently infected cells and induced transient quantifiable plasma viremia," and "phenotypic changes occurred in the T-cell compartment during romidepsin treatment," the researchers summarized. However, "the HIV-1 reservoir was not significantly reduced by romidepsin."
"We have enough data to say the agent was successful in doing what it was supposed to: kicking virus out of cells," Søgaard said at an International AIDS Society "Towards an HIV Cure" press briefing. "We can make cells release virus into plasma, but that may not be enough to reduce the reservoir."
This data offers "the first evidence that we can identify the latent reservoir and shock it out of hiding in people," Steven Deeks of the University of California at San Francisco said at the briefing. "That is the single most important advance of this meeting and it will have a major impact in the future." That's the shock, he said, "but once [the virus] gets out, we have to kill it."
Deeks, like most others working on HIV cure research, thinks a combination approach will be necessary to achieve a functional cure that allows people with HIV to remain off ART without disease progression. As virus is released from resting cells, the immune system will need to be able to recognize and attack it.
Søgaardsaid his team have just started enrolling participants in a new study looking at romidepsin in combination with the Vacc-4x therapeutic HIV vaccine.
OS Søgaard, ME Graversen, S Leth, et al. The HDAC inhibitor romidepsin is safe and effectively reverses HIV-1 latency in vivo as measured by standard clinical assays. 20th International AIDS Conference (AIDS 2014). Melbourne, July 20-25, 2014. Abstract TUAA0106LB.
Aarhus University. Anti-cancer drug kicks HIV out of hiding. Press release. July 22, 2014.