Deacetylase Inhibitor Both Actives Latent CD4 Cells and Reduces Coreceptor
A histone deacetylase (HDAC) inhibitor that turns off suppression
of latent HIV genes in resting CD4 T-cells has the potential
to flush hidden virus out of reservoir cells and make it vulnerable
to antiretroviral drugs, according to a laboratory study published
in the May
2010 Journal of Acquired Immune Deficiency Syndromes.
Researchers found that the HDAC inhibitor ITF2357 increased
HIV gene expression up to 15-fold more that the related agent
do not fully understand how HIV evades immune responses and establishes
itself in long-lived resting T-cells, but various signalling molecules
and transcription factors appear to play a role.
Chromatin-associated repression -- or interference with the DNA/protein
structures that make up chromosomes -- is one such mechanism that maintains
HIV latency. Histones, the major protein in chromatin, are surrounded
by DNA and play a key role in regulating gene expression.
Inactive HIV manages to turn off expression of its genes and exists
as proviral DNA integrated into the chromosome of the latent host cell.
Various triggers can wake up latent cells and cause them to begin producing
new virus, which is how HIV is able to evade eradication even by fully
suppressive antiretroviral therapy.
In an effort to activate and flush out quiescent HIV, Shay Matalon from
the University of Colorado and colleagues performed a laboratory study
to evaluate ITF2357, a histone deacetylase (HDAC) inhibitor. HDAC inhibitors
work by reversing the repression of HIV gene expression, the study authors
explained. Once a CD4 T-cell becomes activated and begins producing
virus, it soon becomes exhausted and dies.
trials of another HDAC inhibitor, valproic acid, did not substantially
reduce the pool of latent CD4 cells containing HIV provirus, the investigators
noted as background.
In the present study, they compared the effectiveness of valproic acid
and ITF2357 -- an orally active agent considered to be generally safe
and well-tolerated -- for forcing HIV expression in latently infected
cells in vitro. This was determined by measuring levels of p24, an HIV
protein released when HIV breaks apart its inner capsid during replication.
In addition, the study authors also looked at the effect of ITF2357
on cell surface expression of the co-receptors CCR5 and CXCR4, which
HIV uses along with the CD4 receptor to enter cells. Peripheral blood
mononuclear cells from HIV negative donors were treated with ITF2357,
and coreceptor expression was measured using flow cytometry.
clinically relevant concentrations, ITF2357 increased p24 levels
by 15-fold in one laboratory cell line (ACH2 cells) and by 9-fold
in another (U1 cells).
contrast, valproic acid increased expression by less than 2-fold
in both types of cells.
analogs that mainly targeted HDAC-1 increased p24 levels by up to
CD4 cells treated with ITF2357, expression of CXCR4 decreased by
on these findings the study authors wrote, "ITF2357 is superior
to valproic acid in inducing HIV-1 from latently infected cells."
"Safely used in humans, ITF2357 is an attractive candidate for
HIV-1 clinical purging," they concluded.
Investigator affiliation: Department of Medicine, University of Colorado
Denver, Denver, CO.
Matalon, BE Palmer, MF Nold, and others. The histone deacetylase inhibitor
ITF2357 decreases surface CXCR4 and CCR5 expression on CD4(+) T-cells
and monocytes and is superior to valproic acid for latent HIV-1 expression
in vitro. Journal of Acquired Immune Deficiency Syndromes 54(1): 1-9