AI Article Synopsis

  • Chromatin-associated repression helps maintain HIV-1 latency, and inhibiting histone deacetylases (HDAC) can reactivate the virus from quiescent cells.
  • The study compared the effects of ITF2357 (an effective HDAC inhibitor) with valproic acid (VPA) to see which better triggers HIV-1 expression in latently infected cells.
  • Results showed ITF2357 significantly increased viral protein expression compared to VPA and also decreased a specific cell surface receptor (CXCR4), making it a promising option for clinical HIV-1 treatment.

Article Abstract

Objectives: Chromatin-associated repression is one mechanism that maintains HIV-1 latency. Inhibition of histone deacetylases (HDAC) reverses this repression resulting in viral expression from quiescently infected cells. Clinical studies with the HDAC inhibitor valproic acid (VPA) failed to substantially decrease the latent pool within resting CD4(+) cells. Here we compared the efficacy of ITF2357, an orally active and safe HDAC inhibitor, with VPA for HIV-1 expression from latently infected cells in vitro. We also evaluated the effect of ITF2357 on the surface expression of CXCR4 and CCR5.

Methods: Latently infected cell lines were incubated with either ITF2357 or VPA and p24 levels were measured. Peripheral blood mononuclear cells of uninfected donors were treated with ITF2357 and HIV-1 coreceptors expression was assessed by flow cytometry.

Results: At clinically relevant concentrations, ITF2357 increased p24 by 15-fold in ACH2 cells and by 9-fold in U1 cells, whereas VPA increased expression less than 2-fold. Analogues of ITF2357 primarily targeting HDAC-1 increased p24 up to 30-fold. In CD4(+) T cells treated with ITF2357, CXCR4 expression decreased by 54% (P < 0.001).

Conclusion: ITF2357 is superior to VPA in inducing HIV-1 from latently infected cells. Safely used in humans, ITF2357 is an attractive candidate for HIV-1 clinical purging.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3534976PMC
http://dx.doi.org/10.1097/QAI.0b013e3181d3dca3DOI Listing

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