Researchers
Explore Agents that Reduce CD4 Cell Reservoir and Activate Latent
HIV
SUMMARY
A gold compound, auranofin, can kill memory CD4 T-cells
that harbor latent HIV, thereby depleting the viral reservoir,
according to a recent study. Other researchers used a
high-throughput screen to identify compounds that can
flush latent virus out of reservoir cells. |
By
Liz Highleyman
Over
the past few years a growing body of research has looked at
ways
to cure HIV, aiming either to completely eradicate the
virus or produce a "functional cure" that enables
people with HIV to safely
stop antiretroviral
therapy (ART).
One
of the key obstacles to reaching this goal is the fact that
HIV genetic material (known as proviral DNA) can integrate
itself and remain dormant in a "reservoir" of resting
cells -- primarily long-lived memory CD4 T-cells -- where
it is unreachable by current antiretroviral drugs. Researchers
have proposed reducing this reservoir by either activating
resting cells to "purge" or "flush out"
latent virus, or by killing off resting cells that contain
integrated viral DNA.
New
Activating Agent
A study described in the April
15, 2011, advance online edition of the Journal of Biological
Chemistry took the first approach, looking for compounds
that could activate and purge latent HIV.
Sofiya Micheva-Viteva from Los Alamos National Laboratory
and colleagues devised a cell-based system to model HIV latency
in the laboratory. They used this model with a high-throughput
screen to identify small molecules that could antagonize,
or reverse, HIV latency.
They identified a compound dubbed antiviral 6 (AV6) that reproducibly
activated latent proviral DNA from different lymphocyte-based
laboratory cell lines and from latently infected primary (taken
from people) resting CD4 T-cells. AV6 did not, however, cause
dangerous generalized T-cell proliferation or activation.
Furthermore, they also showed that AV6 complemented the ability
of a previously known histone deacetylase (HDAC) inhibitor
to activate latent HIV.
Based on these results, the investigators concluded, "This
is a proof of concept showing that [a high-throughout screen]
employing a cell-based model of HIV-1 latency can be utilized
to identify new classes of compounds with novel activities
that can be used in concert with other persistence antagonists
with the aim of viral clearance."
Auranofin
As
described in the April
18, 2011, advance online edition of AIDS, Mark
Lewis, Andrea Savarino, and colleagues tried the second approach,
testing whether auranofin (brand name Ridaura) -- a gold compound
used to treat rheumatoid arthritis -- could help deplete the
reservoir of T-cells harboring HIV.
The
researchers first exposed primary human CD4 T-cells to auranofin
in a laboratory study. They found that auranofin promoted
cell differentiation, changing the phenotype (markers identifying
cell function) of naive, central memory, and transitional
memory T-cells. The compound also caused cell death, which
was more pronounced for memory cells -- the type most likely
to contain latent virus.
They next tested whether auranofin could reduce the viral
DNA reservoir in a pilot study of 6 macaque monkeys infected
with SIV, a primate relative of HIV. At the start of the experiment
the macaques had stably suppressed viral load on standard
ART consisting of tenofovir (Viread, also in the Truvada and
Atripla coformulations), emtricitabine (Emtriva), and the
integrase inhibitor raltegravir (Isentress).
Auranofin significantly decreased viral DNA in peripheral
blood cells of monkeys on 3-drug ART, though the effect was
transient. The gold compound shortened the lifespan and reduced
the population size of central memory CD4 T-cells, while not
significantly diminishing the naive CD4 T-cell population.
Overall CD4 cell counts remained stable.
When ART was intensified by adding ritonavir-boosted darunavir
(Prezista), the decrease in SIV DNA was sustained through
11 weeks in auranofin-treated monkeys, but not in a control
group on intensified ART alone. Macaques on intensified ART
were then treated with the HDAC inhibitor vorinostat at week
10 to see if it could flush out any remaining latent virus.
Viral rebound did not occur in monkeys that took auranofin,
although it did in control monkeys.
After all treatment was suspended, monkeys that had received
auranofin experienced delayed and lower-level viral load rebound
after about 7 weeks, compared with less than 2 weeks for control
monkeys. One animal maintained a low viral load and stable
high CD4 count for nearly a year, Savarino reported.
"These findings represent a first step towards a remission
of primate lentiviral infections," the study authors
optimistically concluded.
Nevertheless, in a press release describing the research,
Savarino cautioned that people with HIV should not yet try
this approach using off-label auranofin. "I strongly
recommend that people living with HIV/AIDS do not buy the
drug from uncontrolled sources such as the e-Bay and start
self-treatment outside highly medicalized settings,"
he stated.
Investigator affiliations:
Micheva-Viteva study: Los Alamos National Laboratory, Los
Alamos, NM; Robert Wood Johnson Medical School-University
of Medicine and Dentistry of New Jersey, Piscataway, NJ; Memorial
Sloan-Kettering Cancer Center, New York, NY; PTC Therapeutics,
Inc., South Plainfield, NJ.
Lewis study: BIOQUAL, Inc., Rockville, MD; VGTI-Florida, Port
St. Lucie, FL; Cenci-Bolognetti Foundation, Dept of Public
Health Sciences, Sapienza University of Rome, Rome, Italy;
IRCCS San Raffaele Pisana, Rome, Italy; Cenci-Bolognetti Foundation,
Dept of Drug Chemistry and Technologies, Sapienza University
of Rome, Rome, Italy; Istituto Superiore di Sanità,
Rome, Italy.
4/29/11
References
S
Micheva-Viteva, Y Kobayashi, LC Edelstein, et al. High-throughput
screening uncovers a compound that activates latent HIV-1
and acts cooperatively with a HDAC inhibitor. Journal of
Biological Chemistry (abstract).
April 15, 2011 (Epub ahead of print).
MG
Lewis, S Dafonseca, N Chomont, et al. Gold drug auranofin
restricts the viral reservoir in the monkey AIDS model and
induces containment of viral load following ART suspension.
AIDS (abstract).
April 18, 2011 (Epub ahead of print).
Other
Source
A Savarino. Gold-based Drug to Hit HIV Reservoirs. Press release.
April 20, 2011.
