TY - JOUR
T1 - Determinants of the efficacy of HIV latency-reversing agents and implications for drug and treatment design
AU - Ke, Ruian
AU - Conway, Jessica M.
AU - Margolis, David M.
AU - Perelson, Alan S.
PY - 2018/10/18
Y1 - 2018/10/18
N2 - 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.
AB - 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.
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U2 - 10.1172/jci.insight.123052
DO - 10.1172/jci.insight.123052
M3 - Article
C2 - 30333308
AN - SCOPUS:85063244074
SN - 2379-3708
VL - 3
JO - JCI Insight
JF - JCI Insight
IS - 20
ER -