The mathematical analysis of plasma HIV-1 viral load decay after the initiation of antiretroviral therapy has led to a number of important insights abou the dynamics and pathogenesis of HIV infection. With protease inhibitor and reverse transcriptase inhibitor therapies a now classic biphasic decay of HIV RNA was discovered and interpreted using simple viral dynamic models. These models suggested that the first phase was due to the rapid death of productively infected cells and that the second phase was due to the death of long-lived infected cells. Remarkably, the same simple model that accounted for first phase decay when perturbed by therapy could also account for the kinetics of acute infection observed using sparsely sampled data, mostly collected after the viral load peak. Now new data is available that allows us to gain new insights into both acute infection and long-term drug therapy. First, data from acutely infected individuals with very frequent sampling is available from the Early Capture HIV Cohort (ECHO/RV127) study. This study follows participants at high risk for HIV infection twice weekly. Once identified as being HIV-infected, individuals are sampled twice weekly for a month, then weekly for another month, then monthly for 5 years in order to obtain information on clinical consequences. The original model of acute infection dynamics fits much of this data poorly, suggesting acute infection kinetics are not yet fully understood, particularly with regard to immune system influences. Secondly, new frequently collected data from an ACTG study in which treatment na?ve patients were given raltegravir plus emtricitabine/tenofovir uncovered that the first phase has two parts: a rapid phase of decay over the first few days of therapy (phase 1a) followed by a slower phase 1b. Using single copy assays, a very slow 3rd phase of decay (t1/2=39 wks) followed by a 4th phase of stable viremia has been identified, the origins of which are not understood. Here we aim to uncover through modeling the biological basis of acute infection dynamics and these newly observed short and long term HIV dynamics under therapy, and their implications for treatment and viral eradication.

Public Health Relevance

This work will increase our understanding of acute HIV infection dynamics and the immunological factors that influence early infection and the establishment of viral reservoirs. Our proposed work will provide new insights into the compartments responsible for the kinetics of decay observed with raltegravir and into the reservoirs that prevent long-term viral eradication with current therapies.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01AI028433-24
Application #
8701212
Study Section
AIDS Clinical Studies and Epidemiology Study Section (ACE)
Program Officer
Gezmu, Misrak
Project Start
Project End
Budget Start
Budget End
Support Year
24
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Los Alamos National Lab
Department
Type
DUNS #
City
Los Alamos
State
NM
Country
United States
Zip Code
87545
Canini, Laetitia; Chatterjee, Anushree; Guedj, Jeremie et al. (2015) A pharmacokinetic/viral kinetic model to evaluate the treatment effectiveness of danoprevir against chronic HCV. Antivir Ther 20:469-77
Sherman, Kenneth E; Guedj, Jeremie; Shata, Mohamed Tarek et al. (2014) Modulation of HCV replication after combination antiretroviral therapy in HCV/HIV co-infected patients. Sci Transl Med 6:246ra98
Graw, Frederik; Balagopal, Ashwin; Kandathil, Abraham J et al. (2014) Inferring viral dynamics in chronically HCV infected patients from the spatial distribution of infected hepatocytes. PLoS Comput Biol 10:e1003934
Conway, Jessica M; Perelson, Alan S (2014) A hepatitis C virus infection model with time-varying drug effectiveness: solution and analysis. PLoS Comput Biol 10:e1003769
Canini, Laetitia; Perelson, Alan S (2014) Viral kinetic modeling: state of the art. J Pharmacokinet Pharmacodyn 41:431-43
Ciupe, Stanca M; Ribeiro, Ruy M; Perelson, Alan S (2014) Antibody responses during hepatitis B viral infection. PLoS Comput Biol 10:e1003730
Song, Hongshuo; Hora, Bhavna; Bhattacharya, Tanmoy et al. (2014) Reversion and T cell escape mutations compensate the fitness loss of a CD8+ T cell escape mutant in their cognate transmitted/founder virus. PLoS One 9:e102734
Rotman, Yaron; Noureddin, Mazen; Feld, Jordan J et al. (2014) Effect of ribavirin on viral kinetics and liver gene expression in chronic hepatitis C. Gut 63:161-9
Althaus, Christian L; Joos, Beda; Perelson, Alan S et al. (2014) Quantifying the turnover of transcriptional subclasses of HIV-1-infected cells. PLoS Comput Biol 10:e1003871
Fletcher, Courtney V; Staskus, Kathryn; Wietgrefe, Stephen W et al. (2014) Persistent HIV-1 replication is associated with lower antiretroviral drug concentrations in lymphatic tissues. Proc Natl Acad Sci U S A 111:2307-12

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