HIV-1 expression within resting CD4+ T cells after multiple doses of vorinostat

Abstract

Background: A single dose of the histone deacetylase inhibitor vorinostat (VOR) up-regulates HIV RNA expression within resting CD4(+) T cells of treated, aviremic human immunodeficiency virus (HIV)-positive participants. The ability of multiple exposures to VOR to repeatedly disrupt latency has not been directly measured, to our knowledge.

Methods: Five participants in whom resting CD4(+) T-cell-associated HIV RNA (rc-RNA) increased after a single dose of VOR agreed to receive daily VOR Monday through Wednesday for 8 weekly cycles. VOR serum levels, peripheral blood mononuclear cell histone acetylation, plasma HIV RNA single-copy assays, rc-RNA, total cellular HIV DNA, and quantitative viral outgrowth assays from resting CD4(+) T cells were assayed.

Results: VOR was well tolerated, with exposures within expected parameters. However, rc-RNA measured after dose 11 (second dose of cycle 4) or dose 22 (second dose of cycle 8) increased significantly in only 3 of the 5 participants, and the magnitude of the rc-RNA increase was much reduced compared with that after a single dose. Changes in histone acetylation were blunted. Results of quantitative viral outgrowth and other assays were unchanged.

Conclusions: Although HIV latency is disrupted by an initial VOR dose, the effect of subsequent doses in this protocol was much reduced. We hypothesize that the global effect of VOR results in a refractory period of ≥ 24 hours. The optimal schedule for VOR administration is still to be defined.

Keywords: HDAC inhibitor; HIV; acetylation; histone; latency; vorinostat.

Figure 1.

Protocol schema for multiple-dose vorinostat testing. Abbreviations: CA-RNA, cell-associated HIV RNA; IUPM, infected units per million; M, Monday; T, Tuesday; VOR, vorinostat; W, Wednesday.

Figure 2.

Exposures to vorinostat (VOR) at weeks 4 and 8 are similar to single-dose exposure. Abbreviations: AUC, area under the receiver operating characteristic curve; C_max, maximum concentration; IQR, interquartile range; PK, pharmacokinetics.

Figure 3.

A, Relative human immunodeficiency virus (HIV) 1 gag RNA copies per million resting CD4⁺ T cells at study baseline and after doses 11 and 22. *P < .05 (significant increase from baseline; Mann–Whitney test). B, Fold change from baseline of relative HIV-1 gag RNA copies per million resting CD4⁺ T cells (blue) and total H3 acetylation in small lymphocytes (red) at baseline and after doses 11 and 22 (single-dose data from Archin et al [14]).

Figure 4.

The frequency of replication-competent human immunodeficiency virus infection within resting CD4⁺ T cells was measured at baseline and after doses 11 and 22. Abbreviations: IUPM, infectious units per billion; VOR, vorinostat.