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JCI Insight. 2018 Oct 18;3(20). pii: 123052. doi: 10.1172/jci.insight.123052.

Determinants of the efficacy of HIV latency-reversing agents and implications for drug and treatment design.

Author information

1
Department of Mathematics, North Carolina State University, Raleigh, North Carolina, USA.
2
Theoretical Biology and Biophysics Group, MS-K710, Los Alamos National Laboratory, Los Alamos, New Mexico, USA.
3
Department of Mathematics and Center for Infectious Disease Dynamics, Pennsylvania State University, State College, Pennsylvania, USA.
4
University of North Carolina (UNC) HIV Cure Center, UNC Institute of Global Health and Infectious Diseases.
5
Departments of Medicine, Microbiology and Immunology, UNC Chapel Hill School of Medicine, and.
6
Department of Epidemiology, UNC Chapel Hill School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Abstract

HIV eradication studies have focused on developing latency-reversing agents (LRAs). However, it is not understood how the rate of latent reservoir reduction is affected by different steps in the process of latency reversal. Furthermore, as current LRAs are host-directed, LRA treatment is likely to be intermittent to avoid host toxicities. Few careful studies of the serial effects of pulsatile LRA treatment have yet been done. This lack of clarity makes it difficult to evaluate the efficacy of candidate LRAs or predict long-term treatment outcomes. We constructed a mathematical model that describes the dynamics of latently infected cells under LRA treatment. Model analysis showed that, in addition to increasing the immune recognition and clearance of infected cells, the duration of HIV antigen expression (i.e., the period of vulnerability) plays an important role in determining the efficacy of LRAs, especially if effective clearance is achieved. Patients may benefit from pulsatile LRA exposures compared with continuous LRA exposures if the period of vulnerability is long and the clearance rate is high, both in the presence and absence of an LRA. Overall, the model framework serves as a useful tool to evaluate the efficacy and the rational design of LRAs and combination strategies.

KEYWORDS:

AIDS/HIV; Drug therapy; Therapeutics

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