By
Liz Highleyman
Current
antiretroviral
drugs do a good job of stopping HIV replication in the
blood, but they cannot reach the latent "reservoir"
of virus hidden in long-lived inactive CD4 T-cells. Furthermore,
as long as this virus remains hidden, it can evade immune
surveillance and rebound rapidly if treatment
is interrupted.
Researchers
have proposed various strategies for activating these cells
and thereby releasing the sequestered virus, but complete
eradication -- a cure -- has proven elusive.
In
the present study, Robert Siliciano from Johns Hopkins University
and colleagues aimed to find a better method of re-activating
latent HIV, since non-specific or global activation of T-cells
has unacceptable adverse effects associated with cytokines
(chemical messengers) that trigger a systemic inflammatory
response.
The
researchers developed a novel in vitro model of HIV-1
latency. In a laboratory study, human primary CD4 T-cells
were transduced with the "pro-survival" protein
Bcl-2, which inhibits apoptosis, or "cell suicide,"
through the interleukin-7 (IL-7) signalling pathway. The
resulting cells over-expressed Bcl-2, allowing them to mimic
the sustained "quiescent" or inactive state of
resting CD4 cells in the body.
The
investigators then used this model system to search for
agents that could reverse viral latency, screening some
2400 small-molecule compounds.
Results
 |
17
compounds were identified that stimulated HIV re-activation
and replication. |
|
The
most active compound -- 5-hydroxynaphthalene-1,4-dione
(5HN), derived from the black walnut tree -- reactivated
latent HIV without causing global T-cell activation.
|
|
Unlike
previously described latency-reversing agents, 5HN activated
latent HIV-1 through reactive oxygen species (ROS) and
nuclear factor kappa-B (NF-kappa-B). |
|
The
new compound, however, did not affect nuclear factor
of activated T-cells (NFAT) or protein kinase C theta
(PKC-theta). |
These
results, the study authors wrote, demonstrate that T-cell
receptor signalling pathways "can be dissected and
utilized to purge latent virus."
"Our
study expands the number of classes of latency-reversing
therapeutics and demonstrates the utility of this in vitro
model for finding strategies to eradicate HIV-1 infection,"
they concluded.
"Because
of the high cost and potential toxicities of long-term HAART
and the disappointing results from the clinical trials of
HIV-1 vaccines and microbicides, there is still a pressing
need for pursuing the goal of eradication," the researchers
elaborated in their discussion.
"To
cure HIV-1 infection is exceptionally challenging and will
likely require combining HAART with agents that can purge
latent virus," they continued. "Although the toxicities
of 5HN raise concerns for its clinical application, this
is a proof of concept for this approach to finding novel
strategies to reactivate latent HIV-1 without inducing global
T-cell activation."
On a cautionary noted, Siliciano pointed out that recent
research indicates that there appears to also be a second,
not yet identified, HIV reservoir, and achieving a cure
may require finding ways to target this reservoir as well.
Department
of Medicine and Department of Pharmacology and Molecular
Sciences, Johns Hopkins University School of Medicine, Baltimore,
MD; Department of Biology, Calvin College, Grand Rapids,
MI; Department of Molecular Microbiology and Immunology,
Johns Hopkins University Bloomberg School of Public Health,
Baltimore, MD; Howard Hughes Medical Institute, Baltimore,
MD.
10/16/09
Reference
HC
Yang, S Xing, L Shan, and others. Small-molecule screening
using a human primary cell model of HIV latency identifies
compounds that reverse latency without cellular activation.
Journal of Clinical Investigation. October 1, 2009 (epub
ahead of print). (Free
full text).
