Determinants of the efficacy of HIV latency-reversing agents and implications for drug and treatment design
Ruian Ke, Jessica M. Conway, David M. Margolis, Alan S. Perelson
Ruian Ke, Jessica M. Conway, David M. Margolis, Alan S. Perelson
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Research Article AIDS/HIV Therapeutics

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

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.

Authors

Ruian Ke, Jessica M. Conway, David M. Margolis, Alan S. Perelson

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Figure 1

Diagram of a compartmental model for the dynamics of the HIV latent reservoir on and after latency reversing agent (LRA) exposure.

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Diagram of a compartmental model for the dynamics of the HIV latent rese...
In the absence of an LRA, the unactivated (resting) latently infected cell population (L and blue dots) is affected by cell proliferation, natural cell death, and natural cell activation (at per capita rates, ρ, d, and η, respectively). Upon LRA exposure, latently infected cells become induced (A and red dots) at per capita rate α (i.e., the latency reversal [LR] rate). Over time, the induced cells either are killed/cleared by immune effector cells at per capita rate δ (i.e., the clearance rate) or lose induction and become refractory to further immediate latency reversal (R and green dots) at per capita rate γ (the exit rate). Cells in a refractory state return to the latent but responsive state (L) at rate ω. After LRA exposure, if induced cells stay in the induced state, e.g., HIV antigen is continuously expressed on the cell surface, induced cells can still be cleared by immune effector cells; otherwise, they become refractory to LRA and eventually return to an unactivated state. A second cycle of LRA treatment may then proceed, leading to further reduction in the reservoir size. All latently infected cells proliferate at per capita rate ρ.