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 HIV and Hepatitis.com Coverage of the
XVIII International AIDS Conference
(AIDS 2010)  July 18 - 23, 2010, Vienna, Austria
Histone Deacetylase Inhibitor Both Actives Latent CD4 Cells and Reduces Coreceptor Expression

SUMMARY: 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 valproic acid.

Researchers 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.

Clinical 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.

Results

At 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).
In contrast, valproic acid increased expression by less than 2-fold in both types of cells.
ITF2357 analogs that mainly targeted HDAC-1 increased p24 levels by up to 30-fold.
In CD4 cells treated with ITF2357, expression of CXCR4 decreased by 54%.

Based 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.

7/20/10

Reference
S 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 (Abstract). May 2010.


 

 

 

 

 

 

 

 

 

 

 



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