A compartment based model for the formation of 2-LTR circles after raltegravir intensification

Cardozo, E. Fabián; Vargas, Cesar A.; Zurakowski, Ryan

doi:10.1109/cdc.2012.6426088

Cited by 7 publications

(9 citation statements)

References 23 publications

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“…While several studies have failed to show evidence of ongoing cycles of HIV-1 infection due to the lack of plasma viral load changes under the conditions described in Buzon et al [13, 15, 16], the absence of significant changes in plasma HIV-1 is not inconsistent with the existence of ongoing replication in compartments with limited communication with the plasma [13, 15, 17, 16]. There is evidence that viral replication is compartmentalized, isolated by possible barriers between plasma and certain tissues and organs [18, 19].…”

Section: Introductionmentioning

confidence: 99%

Spatial modeling of HIV cryptic viremia and 2-LTR formation during raltegravir intensification

Cardozo

Luo

Piovoso

et al. 2014

Journal of Theoretical Biology

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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 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. Other work has suggested that lymphoid organs may be a site of reduced antiviral penetration and increased viral production. In this study we model the hypothesis that this ongoing replication occurs in lymphoid follicle sanctuary sites and investigate the patterns of 2-LTR formation expected after raltegravir application. Experimental data is used to estimate the reaction and diffusion parameters in the model, and Monte-Carlo simulations are used to explore model behavior subject to variation in these rates. The results suggest that conditions for the formation of an observed transient peak in 2-LTR formation following raltegravir intensification include a sanctuary site diameter larger than 0.2 mm, a viral basic reproductive ratio within the site larger than 1, and a total volume of active sanctuary sites above 20 mL. Significant levels of uncontrolled replication can occur in the sanctuary sites without measurable changes in the plasma viral load. By contrast, subcritical replication (where the basic reproductive ratio of the virus is less than 1 in all sites) always results in monotonic increases of measured 2-LTR following raltegravir intensification, occurring at levels below the limit of detection.

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Section: Introductionmentioning

confidence: 99%

Spatial modeling of HIV cryptic viremia and 2-LTR formation during raltegravir intensification

Cardozo

Luo

Piovoso

et al. 2014

Journal of Theoretical Biology

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“…We had previously shown that a model with high levels of ongoing virus replication prior to raltegravir intensification was capable of producing these dynamics, while models with moderate or low levels of virus replication were consistent only with monotonic responses [7], [17]. In this paper, we have applied monotone system theory to exhaustively consider all hypotheses consistent with an absence of viral replication prior to raltegravir intensification.…”

Section: Discussionmentioning

confidence: 92%

“…Low level viremia is almost always detectable using ultrasensitive assays [6]. Possible explanations for the persistent viral presence are the activation of stable viral reservoirs as for example latently infected memory-phenotype CD4+ T cells, on-going viral replication possibly in a sanctuary site such as lymph nodes [7], or some combination of both [8], [9]. Sharkey et al [10], present evidence for continued replication in cryptic reservoirs of patients whose viral loads are below the standard lower limit of detection.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of HIV 2-LTR formation models using monotone system theory

Piovoso

Zurakowski

2014

2014 American Control Conference

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An important question in HIV research is whether the combination Antiretroviral Therapy (cART) is capable of fully suppressing the replication of HIV virus. Recent experiments have tested whether this is the case by perturbing the virus dynamics in patients with apparently suppressed HIV replication, as measured by blood viremia levels, by adding an integrase inhibitor raltegravir to the existing cART regimen. Following the addition of raltegravir, a consistent spike followed by decay was observed in the concentrations of a HIV DNA artifact marker, the 2-LTR circle. In previous work, we have shown that a model of ongoing HIV replication explains this behavior, while a model of controlled or absent HIV replication does not. A recent paper by Angeli and Sontag (2012) describes a method of invalidating biological models with sign-definite interactions by considering the monotonicity of the observed outputs relative to the monotonicity of the network description of the model. In this paper, we use this method to evaluate alternative explanations of the observed 2-LTR behavior. We show via monotone system theory that models consistent with the observed non-monotonic response in measured 2-LTR are either biologically infeasible or contain ongoing viral replication.

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“…We use the multicompartmental model proposed in [44, 32] configured with one main compartment representing the blood, the high endothelial venules and the lymphatic vessels; and N secondary disconnected spherical compartments representing all the lymph nodes’ follicular sites in the human body. In the model we do not explicitly coded each of the N secondary compartments, rather we assume that all of them have the same dynamics.…”

Section: Approachmentioning

confidence: 99%

“…In this paper, we use a multi-compartmental model that was presented in previous studies [44, 32]. In addition, we do a theoretical analysis of the model to find those conditions that guarantee that the virus is suppressed (not eliminated) in all compartments, and this provides an initial state of the system.…”

Section: Introductionmentioning

confidence: 99%

Increased inflammation in sanctuary sites may explain viral blips in HIV infection

2016

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Combined antiretroviral therapy (cART) is a powerful therapy to suppress HIV-1 viral replication. Although in treatment, viral load in plasma remains below the limit of detection in regular assays, 50copiesmL, intermittent episodes of transient viremia (viral blips) over the limit of detection occur in a significant set of HIV-patients under cART. Here, we develop a model-based study of a possible relation between ongoing replication in lymphoid-tissue-based sanctuary sites and viral blips. Given that follicular hyperplasia occurs during lymphoid inflammation as a normal response to infection, we hypothesize that when the diameter of the lymph node follicle increases and crosses a critical size, a viral blip occurs due to cryptic viremia. To demonstrate this we do a theoretical analysis of the model to find those conditions that guarantee that the virus is suppressed in all compartments, and simulate the model for different scenarios of lymph node follicle diameter changes. Thus, to have realistic viral blips, with duration of less than 30 days and with amplitudes relatively close to the limit of detection, the diameter rise rate should be between 0.02 and 0.03 days−1. Moreover, the final diameter of the site is directly related to the steady states of the virus load after the occurrence of a blip. When the steady state viral load after the blip is below the limit of detection, the median value of R0 is 1.45. However, when the median increases beyond 2.1, the steady state of the viral load after the blip often has a value above the limit of detection if the final maximum diameter is sufficiently small. In these cases, for a realistic blip, the maximum final diameters should be greater than 0.7mm so that there is a relative loss of connection between compartments.

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A compartment based model for the formation of 2-LTR circles after raltegravir intensification

Cited by 7 publications

References 23 publications

Spatial modeling of HIV cryptic viremia and 2-LTR formation during raltegravir intensification

Spatial modeling of HIV cryptic viremia and 2-LTR formation during raltegravir intensification

Evaluation of HIV 2-LTR formation models using monotone system theory

Increased inflammation in sanctuary sites may explain viral blips in HIV infection

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