Multi-compartmental modeling of HIV-1 cryptic viremia
Date
2014
Authors
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Journal ISSN
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Publisher
University of Delaware
Abstract
Combination Antiretroviral Therapy (cART) can suppress plasma HIV below the limit of detection in normal assays. Recently reported results suggest that viral replication may continue in some patients, despite undetectable levels in the blood. It is broadly reported that latently infected cells are the main cause of this persistence under cART. It has been suggested that the appearance of the circularized episomal HIV DNA artifact 2-LTR, following treatment intensification with the integrase inhibitor raltegravir, is a marker of ongoing viral replication. These 2-LTR episomes are assumed to be formed from the virus DNA copies that could not be integrated in the DNA of the CD4+ T Cells caused by raltegravir. Other work has suggested that lymphoid organs may be a site of reduced antiviral penetration and increased viral production. Given the fact that raltegravir does not affect viral load in peripheral blood, the main hypothesis of viral persistence through ongoing replication is that the process is happening in anatomical reservoirs related to poor penetration of reverse transcriptase and protease inhibitors. This thesis proposes a mathematical model to investigate whether lymph nodes can function as sanctuary sites for ongoing viral replication and investigates the patterns of 2-LTR formation expected after raltegravir application, incorporating spatial dynamics to previous models. It also describes the mechanisms by which this could be possible, and the conditions needed to generate the transient behavior of both measured 2-LTR and HIV viremia in the blood after administering raltegravir in patients on apparently suppressive cART regimens as shown in recent studies. A multi-compartmental differential equation is described taking into account the dynamics of infected and uninfected CD4+ T cells, free virus, and cells containing 2-LTR circles. The sanctuary site is modeled with limited penetration of the antiviral drugs. Experimental data and previously published distributions are used to estimate the reaction and diffusion parameters and HIV and T-cells rates in a Monte-Carlo simulation of the model to determine what parameter values are consistent with the observed 2-LTR transient behavior. This thesis analyzes the effect of different suboptimal penetration of drug in cART, the anatomical reservoir size on cryptic viremia for hyperplastic follicles inside lymph nodes and its possible effect in the formation of viral blips and 2-LTR circles in the blood. Using previous 2-LTR circles data, this thesis presents how these conditions have to be meet in order to have 2-LTR formation in PBMC. Furthermore, through a Bayesian MCMC analysis this thesis aims to find how much T cells recirculation time could affect previous estimation of 2-LTR circles half-life. Based on that, it finally presents that measurable 2-LTR peaks might be correlated to total infection in the body, but with different patterns of drug penetration combinations and reservoir size for each peak.