We have developed a simple model of the formation of 2-LTR HIV DNA episomes following the addition of integrase inhibitor such as raltegravir to an apparently suppressive antiviral regimen. When 2-LTR concentration data from recent raltegravir intensification experiments is fit to our model, the results strongly suggest that the -LTR episomes are being formed in a compartment where the antiviral drugs are unable to contain HIV replication. The primary research objective of this project is to develop specific testable hypotheses to guide a future clinical validation experiment to confirm these findings. Understanding the mechanisms by which HIV replication may continue in patients with no virus detectable in their blood is critically important to efforts to treat and/or cure HIV infection. If cryptic viremia persists, the HIV-positive patient will eventually develop drug-resistant virus and be forced to switch treatment regimens. The mathematical models developed in the proposed research may provide a minimally invasive experimental method to detect and quantify cryptic viremia. This is a critical first step in being able to study and eliminate this phenomenon in HIV medicine. We will use Bayesian statistics to validate our model against a new dataset, develop model extensions that allow us to plan for other measurements, and develop sampling schedules that optimize the information while minimizing the cost and invasiveness of the experiment.

Public Health Relevance

Recent experimental results suggest that high levels of locally uncontrolled HIV virus replication can continue in patients whose measured blood HIV levels are consistently low. This has significant implications for the durability of antiviral therapy, and fo any attempts to cure HIV infection. If successful, the proposed research will allow detection and monitoring of this phenomenon.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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AIDS Clinical Studies and Epidemiology Study Section (ACE)
Program Officer
Lawrence, Diane M
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University of Delaware
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Biomed Engr/Col Engr/Engr Sta
United States
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Cannon, LaMont; Jagarapu, Aditya; Vargas-Garcia, Cesar A et al. (2017) Implications of Measurement Assay Type in Design of HIV Experiments. Proc IEEE Conf Decis Control 2017:4106-4111
Jagarapu, Aditya; Cannon, LaMont; Zurakowski, Ryan (2017) Experiment Design for Early Molecular Events in HIV Infection. Proc Am Control Conf 2017:122-127
Abraham, George; Jagarapu, Aditya; Cannon, Lamont et al. (2016) Order preservation of expected information content using Unscented Transform approximation of multivariate prior distributions in HIV 2-LTR experiment design. Proc IEEE Conf Decis Control 2016:5597-5602
Cannon, LaMont; Garcia, Cesar Augusto Vargas; Piovoso, Michael J et al. (2016) Prospective HIV Clinical Trial Comparison by Expected Kullback-Leibler Divergence. Proc Am Control Conf 2016:1295-1300
Cardozo, E Fabian; Piovoso, Michael J; Zurakowski, Ryan (2016) Increased inflammation in sanctuary sites may explain viral blips in HIV infection. IET Syst Biol 10:153-66