Effect of histone deacetylase inhibitors on HIV production in latently infected, resting CD4(+) T cells from infected individuals receiving effective antiretroviral therapy

Abstract

Persistence of the latent viral reservoir has been recognized as a major obstacle to eradicating human immunodeficiency virus (HIV) in infected individuals receiving antiretroviral therapy. It has been suggested that histone deacetylase inhibitors (HDACis) may purge HIV in the latent viral reservoir. However, the effect of HDACis on the degree and extent of HIV expression in the latent viral reservoir has not been fully delineated. Here we demonstrate that HDACis do not induce HIV production in the latent viral reservoir of aviremic individuals. Therefore, alternative therapeutic strategies may be necessary to eliminate HIV in the latent viral reservoir.

Figure 1.

Effect of histone deacetylase inhibitors (HDACis; valproic acid [VPA], suberoylanilide hydroxamic acid [SAHA], or oxamflatin) and T-cell mitogens (prostratin or anti-CD3 antibody) on cellular activation and viral production in resting CD4⁺ T cells from aviremic individuals infected with human immunodeficiency virus (HIV). A, Level of cellular activation and proliferation of resting CD4⁺ T cells following treatment with study agents. B, Quantitation of cell-free HIV RNA in the culture supernatants of resting CD4⁺ T cells incubated with the corresponding agents. The median value and interquartile range is shown as dark gray bars and light gray lines, respectively. Undetectable levels of HIV RNA were scored as 19 copies/mL. The Wilcoxon signed rank test was used to compare paired data. C, Relationship between HIV DNA burden and virion production in the latent viral reservoir of aviremic individuals. The correlation between the frequency of cells carrying HIV DNA and the level of virion production by resting CD4⁺ T cells following treatment with study agents is shown. Correlations were determined by the Spearman rank method. D, Examination of viral quasi-species by heteroduplex mobility assay (HMA). Virion-associated HIV RNA from resting CD4⁺ T-cell cultures was subjected to amplification of HIV env by polymerase chain reaction and HMA.