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 on
T-cells, researchers reported on Tuesday at the 20th International AIDS Conference (AIDS 2014) in Melbourne.
This finding suggests that kicking HIV out of hiding will not be adequate for a
functional cure without strengthening immune responses against the virus.
One approach widely used in HIV cure research is known
as 'kick 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 cell 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 his team evaluated the HDAC inhibitor romidepsin,
an anti-cancer 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 living with HIV.
The study included six adults living
with HIV (five men and one 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 one year and a
median CD4 count of 760 cells/mm3. People with significant cardiac
disease or hepatitis B or C co-infection were excluded.
All participants in this
non-randomised intervention trial received three once-weekly infusions of
romidepsin (5 mg/m2) at days 0, 7 and 14.
The researchers found that 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 at 21 days.
Levels of cell-associated HIV RNA in CD4 cells rose
significantly in all study participants after romidepsin administration, with
larger increases seen after the second and third doses compared with the first
dose (more than a threefold mean increase).
Plasma HIV RNA also increased, despite participants
being on ART, reaching quantifiable levels in five of the six participants
using a standard clinical viral load assay.
The researchers saw the greatest activation in the
central memory and 'term diff' subsets of T-cells. 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.
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 cells, did not change. Some participants experienced a
small increase and others saw a decrease – including one with a reduction of
80% – but the overall change was not significant.
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
"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 summarised. 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 on Monday. "We can
make cells release virus into plasma, but that may not be enough to reduce the
offer "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 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. 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 living with HIV to remain off ART without disease
progression. As virus is released from resting cells, the immune system will
need to recognise and attack it.
Søgaard said his team has just started enrolling participants in a new study
looking at romidepsin in combination with a therapeutic HIV vaccine (Vacc-4x).