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

Nature volume 487, pages 482–485 (2012)Cite this article

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An Erratum to this article was published on 15 August 2012

Abstract

Despite antiretroviral therapy, proviral latency of human immunodeficiency virus type 1 (HIV-1) remains a principal obstacle to curing the infection1. Inducing the expression of latent genomes within resting CD4+ T cells is the primary strategy to clear this reservoir2,3. Although histone deacetylase inhibitors such as suberoylanilide hydroxamic acid (also known as vorinostat, VOR) can disrupt HIV-1 latency in vitro4,5,6, 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.

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Figure 1: The relative HIV-1 RNA copy number in resting CD4 + T cells of 16 ART-treated HIV-positive patients with plasma HIV RNA BDL.
Figure 2: VOR exposure and histone acetylation.
Figure 3: VOR upregulates HIV RNA expression.

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Acknowledgements

This study was supported by National Institutes of Health grants AI084553, AI095052 and AI096113, and by a grant from Merck & Co to D.M.M., National Institutes of Health grants RR024383 to the UNC TRaCS Institute, AI50410 to the UNC Center for AIDS Research, and an equipment grant from the James B. Pendleton Charitable Trust. Merck & Co provided VOR. The ClinicalTrials.gov identifier is NCT01319383. We thank N. P. Dahl, R. Sackmann, M. Cheema, A. Wiegand and N. White for technical support, Y. Park and the staff the UNC Blood Bank, R. J. Bedimo and C. M. van der Horst for study oversight, and J. Scepanski and A. Sugarbaker for patient follow-up and study coordination. We thank M. S. Cohen, J. V. Garcia-Martinez, W. C. Greene, J. Karn and R. F. Siliciano for discussions. Finally, we are grateful for the contributions of the patients who have participated in these studies.

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Affiliations

  1. The University of North Carolina at Chapel Hill, Chapel Hill, 27599, North Carolina, USA

    N. M. Archin, A. L. Liberty, A. D. Kashuba, S. K. Choudhary, J. D. Kuruc, A. M. Crooks, D. C. Parker, M. G. Hudgens, J. J. Eron & D. M. Margolis

  2. HIV Drug Resistance Program, NCI, NIH, Frederick, Maryland 21702, USA

    E. M. Anderson, M. F. Kearney & J. M. Coffin

  3. VA San Diego Healthcare System and University of California San Diego, San Diego, 92093, California, USA

    M. C. Strain & D. D. Richman

  4. Harvard School of Public Health, Boston, 02115, Massachusetts, USA

    R. J. Bosch

  5. Merck Research Laboratories, White Horse Junction, 08889, Pennsylvania, USA

    D. J. Hazuda

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  1. N. M. Archin
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  2. A. L. Liberty
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  17. D. M. Margolis
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Contributions

N.M.A., A.L.L., D.C.P., S.K.C., M.C.S., D.D.R., D.J.H. and D.M.M. designed and performed primary study assays and performed study analysis. J.D.K., A.M.C., J.J.E. and D.M.M. designed, implemented and oversaw the clinical protocol. M.G.H. and R.J.B. designed the data analysis. A.D.K. oversaw pharmacokinetic assays and analysed these data. M.F.K., E.M.A. and J.M.C. designed and performed single-copy assays.

Corresponding author

Correspondence to D. M. Margolis.

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Competing interests

D.J.H. is an employee of Merck and Co., and J.J.E. and D.M.M. have received grants and consulting honoraria from Merck and Co. N.M.A., D.J.H. and D.M.M. are co-inventors of a patent for the use of vorinostat in HIV infection, but to lead this study D.M.M. has remanded ownership of this patent to UNC Chapel Hill.

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Archin, N., Liberty, A., Kashuba, A. et al. Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy. Nature 487, 482–485 (2012). https://doi.org/10.1038/nature11286

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