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Wong VC, Fong LE, Adams NM, et al. Quantitative evaluation and optimization of co-drugging to improve anti-HIV latency therapy. Cell Mol Bioeng. 2014;7(3):320-333doi: 10.1007/s12195-014-0336-9.
Wong, V. C., Fong, L. E., Adams, N. M., Xue, Q., Dey, S. S., & Miller-Jensen, K. (2014). Quantitative evaluation and optimization of co-drugging to improve anti-HIV latency therapy. Cellular and molecular bioengineering, 7(3), 320-333. https://doi.org/10.1007/s12195-014-0336-9
Wong, Victor C, et al. "Quantitative evaluation and optimization of co-drugging to improve anti-HIV latency therapy." Cellular and molecular bioengineering vol. 7,3 (2014): 320-333. doi: https://doi.org/10.1007/s12195-014-0336-9
Wong VC, Fong LE, Adams NM, Xue Q, Dey SS, Miller-Jensen K. Quantitative evaluation and optimization of co-drugging to improve anti-HIV latency therapy. Cell Mol Bioeng. 2014 Sep 01;7(3):320-333. doi: 10.1007/s12195-014-0336-9. PMID: 26191086; PMCID: PMC4501041.
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Cell Mol Bioeng. 2014 Sep 01;7(3):320-333. doi: 10.1007/s12195-014-0336-9.

Quantitative evaluation and optimization of co-drugging to improve anti-HIV latency therapy.

Cellular and molecular bioengineering

Victor C Wong, Linda E Fong, Nicholas M Adams, Qiong Xue, Siddharth S Dey, Kathryn Miller-Jensen

Affiliations

  1. Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT 06520 USA.
  2. Department of Biomedical Engineering, Yale University, New Haven, CT 06520 USA.
  3. California Institute for Quantitative Biosciences, University of California, Berkeley, CA 94720 USA.
  4. Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT 06520 USA ; Department of Biomedical Engineering, Yale University, New Haven, CT 06520 USA.

PMID: 26191086 PMCID: PMC4501041 DOI: 10.1007/s12195-014-0336-9

Abstract

Human immunodeficiency virus 1 (HIV) latency remains a significant obstacle to curing infected patients. One promising therapeutic strategy is to purge the latent cellular reservoir by activating latent HIV with latency-reversing agents (LRAs). In some cases, co-drugging with multiple LRAs is necessary to activate latent infections, but few studies have established quantitative criteria for determining when co-drugging is required. Here we systematically quantified drug interactions between histone deacetylase inhibitors and transcriptional activators of HIV and found that the need for co-drugging is determined by the proximity of latent infections to the chromatin-regulated viral gene activation threshold at the viral promoter. Our results suggest two classes of latent viral integrations: those far from the activation threshold that benefit from co-drugging, and those close to the threshold that are efficiently activated by a single drug. Using a primary T cell model of latency, we further demonstrated that the requirement for co-drugging was donor dependent, suggesting that the host may set the level of repression of latent infections. Finally, we showed that single drug or co-drugging doses could be optimized, via repeat stimulations, to minimize unwanted side effects while maintaining robust viral activation. Our results motivate further study of patient-specific latency-reversing strategies.

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