Histone deacetylase inhibitor chidamide promotes reactivation of latent human immunodeficiency virus by introducing histone acetylation

Abstract

Highly active antiretroviral therapy can reduce the human immunodeficiency virus (HIV) viral load in the plasma to undetectable levels. However, because of the presence of latent HIV reservoirs, it is difficult to completely eradicate HIV in infected patients. Our objective was to assess the potency of chidamide, a novel histone deacetylase inhibitor recently approved for cancer treatment by the China Food and Drug Administration, to reactivate latent HIV-1 via histone acetylation. Viral reactivities of chidamide were accessed in 2 latent HIV pseudotype virus cell reporter systems (J-Lat Tat-green fluorescent protein clone A72 and TZM-bl), a latently infected full-length HIV virus cell system (U1/HIV), and resting CD4 T cells from 9 HIV-infected patients under highly active antiretroviral therapy with undetectable viral load. Chidamide was able to increase HIV expression in each cell line, as evidenced by green fluorescent protein, luciferase activity, and p24, as well as to reactivate latent HIV-1 in primary CD4 T cells of HIV-infected patients. Histone acetylation adjacent to the HIV promoter in A72 cells was determined by chromatin immunoprecipitation. Chidamide was able to increase histone H3 and H4 acetylation at the HIV promoter. In brief, chidamide induced the reactivation of latent HIV in pseudotype virus reporter cells, latently infected cells, and primary CD4 T cells, making this compound an attractive option for future clinical trials.

Diversity of small molecule HIV‐1 latency reversing agents identified in low‐ and high‐throughput small molecule screens

“…Latency reversing activity of MS‐275 was examined in combination with other molecules including buthionine sulfoximine, a glutathione‐synthesis inhibitor; prostratin, a nontumor‐promoting phorbol ester; and 5‐aza‐2′deoxycytidine, a DNA demethylating agent, and these studies reported various levels of potency, which is likely the result of differences in HIV‐1 reporter virus at different chromosomal regions. The related compound chidamide (Figure ), showed better cell tolerance than the commonly used broad‐spectrum HDAC inhibitor suberoylanilide hydroxamic acid (SAHA), and was also able to disrupt viral silencing in primary CD4 + T cells isolated from patients …”

The histone deacetylase inhibitor chidamide induces intermittent viraemia in HIV‐infected patients on suppressive antiretroviral therapy

“…Chidamide is a low nanomolar HDAC inhibitor of the benzamide class [10], which was approved in 2014 by the China Food and Drug Administration for use in relapsed or refractory peripheral T-cell lymphoma. Chidamide was demonstrated to reactivate latent HIV-1 in cell line models and in primary CD4 T cells from HIV-1-infected individuals [11,12]. Here, we conducted a phase 1b/2a clinical trial to evaluate the safety and efficacy of chidamide to reverse HIV-1 latency in cART-suppressed patients.…”