Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy

N M Archin, A L Liberty, A D Kashuba, S K Choudhary, J D Kuruc, A M Crooks, D C Parker, E M Anderson, M F Kearney, M C Strain, D D Richman, M G Hudgens, R J Bosch, J M Coffin, J J Eron, D J Hazuda, D M Margolis, N M Archin, A L Liberty, A D Kashuba, S K Choudhary, J D Kuruc, A M Crooks, D C Parker, E M Anderson, M F Kearney, M C Strain, D D Richman, M G Hudgens, R J Bosch, J M Coffin, J J Eron, D J Hazuda, D M Margolis

Abstract

Despite antiretroviral therapy, proviral latency of human immunodeficiency virus type 1 (HIV-1) remains a principal obstacle to curing the infection. Inducing the expression of latent genomes within resting CD4(+) T cells is the primary strategy to clear this reservoir. Although histone deacetylase inhibitors such as suberoylanilide hydroxamic acid (also known as vorinostat, VOR) can disrupt HIV-1 latency in vitro, the utility of this approach has never been directly proven in a translational clinical study of HIV-infected patients. Here we isolated the circulating resting CD4(+) T cells of patients in whom viraemia was fully suppressed by antiretroviral therapy, and directly studied the effect of VOR on this latent reservoir. In each of eight patients, a single dose of VOR increased both biomarkers of cellular acetylation, and simultaneously induced an increase in HIV RNA expression in resting CD4(+) cells (mean increase, 4.8-fold). This demonstrates that a molecular mechanism known to enforce HIV latency can be therapeutically targeted in humans, provides proof-of-concept for histone deacetylase inhibitors as a therapeutic class, and defines a precise approach to test novel strategies to attack and eradicate latent HIV infection directly.

Trial registration: ClinicalTrials.gov NCT01319383.

Figures

Figure 1. The relative HIV-1 RNA copy…
Figure 1. The relative HIV-1 RNA copy number in resting CD4+ T cells of 13 ART-treated HIV+ patients with plasma HIV RNA BDL
Values are calculated by cycle number, and limit of quantitation of cell-associated RNA is 10 copies. Cells were cultured alone (untreated), with VOR 335 nM (VOR), or activated with 3 µg/ml PHA and 60 U/ml IL2 for 6 hours. Data from 16 patients (a), and those who later received in vivo dosing [1 (Δ), 2 (□), 3 (◊), 4 (X), 5 (▽), 6 (❍), 7 (+), and 8 (⨀)] are shown in detail (b, mean and s.d.).
Figure 1. The relative HIV-1 RNA copy…
Figure 1. The relative HIV-1 RNA copy number in resting CD4+ T cells of 13 ART-treated HIV+ patients with plasma HIV RNA BDL
Values are calculated by cycle number, and limit of quantitation of cell-associated RNA is 10 copies. Cells were cultured alone (untreated), with VOR 335 nM (VOR), or activated with 3 µg/ml PHA and 60 U/ml IL2 for 6 hours. Data from 16 patients (a), and those who later received in vivo dosing [1 (Δ), 2 (□), 3 (◊), 4 (X), 5 (▽), 6 (❍), 7 (+), and 8 (⨀)] are shown in detail (b, mean and s.d.).
Figure 2. VOR exposure and histone acetylation
Figure 2. VOR exposure and histone acetylation
Median VOR plasma concentrations in patients 1–8 after a single 400 mg oral dose (circles with range shown) is shown in comparison to mean total cellular acetylated histone H3 in PBMCs (diamonds with s.d. shown), and relative levels of acetylated histone H3 at the human p21 gene promoter in resting CD4+ T cells (bars, mean and s.d.). A significant increase (†) in cellular acetylated histone H3 is seen at 8 hours, p

Figure 3. VOR upregulates HIV RNA expression

Figure 3. VOR upregulates HIV RNA expression

The relative HIV-1 RNA copy number (mean, s.d.)…

Figure 3. VOR upregulates HIV RNA expression
The relative HIV-1 RNA copy number (mean, s.d.) measured in the resting CD4+ T cells of eight HIV+ patients with plasma HIV RNA BDL is shown on background ART and on ART following a single 400 mg oral dose of VOR. For each subject, the differences are significant (p
Comment in
  • HIV: Shock and kill.
    Deeks SG. Deeks SG. Nature. 2012 Jul 25;487(7408):439-40. doi: 10.1038/487439a. Nature. 2012. PMID: 22836995 No abstract available.
  • Viral infection: Coaxing HIV out of hiding.
    Jermy A. Jermy A. Nat Rev Microbiol. 2012 Sep;10(9):596-7. doi: 10.1038/nrmicro2861. Epub 2012 Aug 13. Nat Rev Microbiol. 2012. PMID: 22886238 No abstract available.
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Figure 3. VOR upregulates HIV RNA expression
Figure 3. VOR upregulates HIV RNA expression
The relative HIV-1 RNA copy number (mean, s.d.) measured in the resting CD4+ T cells of eight HIV+ patients with plasma HIV RNA BDL is shown on background ART and on ART following a single 400 mg oral dose of VOR. For each subject, the differences are significant (p

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