Views differ on what might be the most productive approach
towards curing HIV infection, and researchers emphasise that there is still a
great deal of ground to be covered. Tony Fauci, director of the US National Institute
of Allergy and Infectious Diseases, described the 'false start' of the
mid-1990s, when some researchers assumed that viral suppression on HAART, and
the absence of new rounds of infection or evolving HIV DNA, meant that
replication had been halted and that eradication was only a question of waiting
a few years for all the HIV-infected cells to die a natural death. Robert
Siliciano and others soon demonstrated that HIV was infecting cells that might
persist for years, and that estimates of HIV eradication after a few years of
HAART were wildly optimistic.
All researchers agree that a cure, functional or otherwise,
will depend on a combination of approaches. Where they disagree is on the
ingredients of the cocktail.
A cure for every patient will need to start with a prolonged
period of antiretroviral therapy to reduce HIV to undetectable levels. This
period of treatment itself could be important in determining the success of
subsequent drug therapies. Will attempts to purge the HIV reservoir be more
successful in people who began treatment very soon after infection? A French
cohort has produced tantalising data suggesting that some people treated in
acute infection can stop treatment and go for very long periods – an average of
72 months so far – without experiencing viral rebound. What is it about these
people that prevents viral rebound? Is it the time they started treatment, their
genes, or just random chance?
Scientists are also interested to learn whether any form of
intensified antiretroviral drug regimen could shrink the pool of latently
infected cells, making them easier to purge later. So far, studies have shown
little or no impact of regimens drawing on the maximum number of drug classes
on the size of the reservoir of latently infected cells, but further studies
are planned, using more sensitive measurement techniques, to see whether
five-drug combinations that target every possible step in the viral lifecycle
have more effect.
Studies are also underway or planned to determine the extent
to which the viral reservoirs can be emptied by using a range of drugs that
will activate latently infected cells so that they can be identified and killed
by the immune system, or self-destruct.
Sharon Lewin of the Alfred Hospital, Melbourne, described
the range of studies already taking place using compounds called HDAC
inhibitors, which stimulate latently infected cells to begin producing
HIV. A number of experimental studies
with HDAC inhibitors are already underway, most notably with vorinostat (SAHA).
This drug is already approved for the treatment of cutaneous lymphoma, and is
currently undergoing phase II tests for a range of other malignancies, so its
short-term toxicities are well characterised. In vitro toxicity studies suggest
a potential long-term risk of malignancy, but at this point no human studies
have reported an increased risk of malignancy. Sharon Lewin’s team is studying
the effect of 14 days of vorinostat (SAHA) in 20 patients with fully suppressed viral load,
and will measure the effect of vorinostat on cell-associated HIV RNA to
determine the effect of the drug on HIV latency.
Professor David Margolis at the University of North Carolina
is conducting a similar experimental study, measuring the effect of a sequence
of single doses of vorinostat on virus production in up to 20 volunteers with
fully suppressed viral load. Steven Deeks at the University of California San
Francisco is testing the anti-alcohol agent disulfiram, which also activates
latently infected cells. Preliminary data presented at CROI in 2012 showed that
this agent stimulated HIV RNA production in a sub-set of chronically infected
patients who received the drug.
In addition to these agents, there are six or seven known
targets for therapies that could disrupt HIV latency, and in collaboration with
Merck Prof. Margolis's research group has identified 83 compounds with differing mechanisms
of action that are being tested for their potential as disruptors of latency.
Two other companies, Gilead and Janssen-Tibotec, are also engaged in major
screening programmes to identify agents that could contribute towards cure
Ultimately a number of different agents may need to be used
in combination, said Warner Greene of the Gladstone Institute, San Francisco,
in order to target the different points in the transcription pathway that
govern the integration and latency of HIV in cells.
Activating agents might also need to be used in combination
with a therapeutic vaccine to stimulate the immune system to clear the
activated cells, because researchers are still uncertain how long the activated
cells will continue to produce virus once activated, and whether cells which
are not fully activated are nevertheless capable of producing virus that will
go to infect other cells. (Activation is a cycle rather than an on/off
Researchers are also investigating
gene therapy approaches that can gradually establish a pool of
HIV-resistant CD4 cells. This approach is already being studied in people with
HIV, but more work is needed to refine the technique and determine whether this
approach can contribute towards an HIV cure.