Until recently a cure for HIV did not seem possible. However, recent developments suggest that some patients have been cured or demonstrate post-treatment control (PTC) of viremia to undetectable levels, corresponding to a "functional cure". Further, there are important new ideas on how to safely activate the HIV-1 latent reservoir, which is believed to be the main obstacle to HIV-1 eradication from a patient. To advance the goal of cure we need to understand these recent clinical observations in quantitative detail. This grant aims to address this gap in knowledge, by leveraging the power of mathematical modeling to understand the dynamics of PTC and activation of the latent reservoir, to compare different biological mechanisms at play in those phenomena and to propose new protocols to advance the HIV cure agenda. We also propose to use mathematical modeling to advance the cure agenda for another chronic infection, hepatitis C virus (HCV). Our hypotheses are: i) that patients whose latent reservoir decays to sufficiently small levels on treatment are more likely to exhibit PTC, and thus we will develop models to understand the biological and dynamic processes that link latency and PTC;ii) that analyzing viral and infected cell kinetics under new therapeutic protocols aiming at activating latently infected cells will lead to new insights into hw to reduce or eliminate this reservoir, and thus we propose to develop a quantitative understanding of these therapies by modeling clinical trial data;iii) that by modeling the effects of new potent direct-acting antivirals for HCV, which target specific viral proteins and have multiple synergistic effects, we will be able to help design the potent drug combinations that are necessary for HCV cure. Altogether, our objectives are to assist clinical collaborators in studies involving HIV (as well as HCV) whenever we feel that rigorous analysis can lead to new insights or to improved treatments for patients. These studies may also raise interesting theoretical questions and drive future modeling efforts.

Public Health Relevance

HIV-1 is still an important health burden, in terms of mortality, morbidity and financially, in the USA and around the world. We will analyze state-of-the-art therapeutic protocols, which for the first time are aimed at generating a cure or functional cure (when the infection is controlled without treatment) for HIV-1. We will develop models of HIV-1 dynamics in the context of these new protocols to help define those that will provide the most clinical benefit. Similarly, we will develop models of new direct-acting therapeutic agents for hepatitis C virus infection that may help increase the HCV cure rate.

Agency
National Institute of Health (NIH)
Institute
Office of The Director, National Institutes of Health (OD)
Type
Research Project (R01)
Project #
2R01OD011095-22
Application #
8731720
Study Section
Special Emphasis Panel (ZRG1-AARR-K (03))
Program Officer
Chang, Michael
Project Start
1991-04-19
Project End
2019-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
22
Fiscal Year
2014
Total Cost
$444,412
Indirect Cost
$194,412
Name
Los Alamos National Lab
Department
Type
DUNS #
175252894
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
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
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
Hernandez-Vargas, Esteban A; Wilk, Esther; Canini, Laetitia et al. (2014) Effects of aging on influenza virus infection dynamics. J Virol 88:4123-31
Canini, Laetitia; Conway, Jessica M; Perelson, Alan S et al. (2014) Impact of different oseltamivir regimens on treating influenza A virus infection and resistance emergence: insights from a modelling study. PLoS Comput Biol 10:e1003568
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

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