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

Journal Article · · JCI Insight
ORCiD logo [1];  [2]; ORCiD logo [3]; ORCiD logo [4]
  1. North Carolina State Univ., Raleigh, NC (United States). Dept. of Mathematics; Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
  2. Pennsylvania State Univ., University Park, PA (United States). Dept. of Mathematics. Center for Infectious Disease Dynamics
  3. Univ. of North Carolina, Chapel Hill, NC (United States). UNC HIV Cure Center. UNC Inst. of Global Health and Infectious Diseases. School of Medicine. Depts. of Medicine, Microbiology and Immunology. School of Public Health. Dept. of Epidemiology
  4. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
+ Show Author Affiliations

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. Here, 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.

Research Organization:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States); North Carolina State Univ., Raleigh, NC (United States); Pennsylvania State Univ., University Park, PA (United States); Univ. of North Carolina, Chapel Hill, NC (United States)
Sponsoring Organization:
National Inst. of Health (NIH) (United States); National Science Foundation (NSF) (United States); USDOE
Grant/Contract Number:
AC52-06NA25396
OSTI ID:
1480001
Report Number(s):
LA-UR-18-25674
Journal Information:
JCI Insight, Journal Name: JCI Insight Journal Issue: 20 Vol. 3; ISSN 2379-3708
Publisher:
American Society for Clinical InvestigationCopyright Statement
Country of Publication:
United States
Language:
English

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  • L., Nordstrom, Jeffrey; M., Margolis, David; D., Tomaras, Georgia
  • The University of North Carolina at Chapel Hill University Libraries https://doi.org/10.17615/5r0x-ga28
text January 2016
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Systemic HIV and SIV latency reversal via non-canonical NF-κB signalling in vivo journal January 2020
Systemic HIV and SIV latency reversal via non-canonical NF-κB signalling in vivo text January 2020
DNAM-1 Activating Receptor and Its Ligands: How Do Viruses Affect the NK Cell-Mediated Immune Surveillance during the Various Phases of Infection? journal July 2019

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