title: Spatial modeling of HIV cryptic viremia and 2-LTR formation during raltegravir intensification.
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 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 0.2mm, a viral basic reproductive ratio within the site larger than 1, and a total volume of active sanctuary sites above 20mL. 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.
authors.affiliation: Electrical and Computer Engineering Department, University of Delaware, DE, United States.
authors.forename: E Fabian
authors.initials: EF
authors.lastname: Cardozo
authors.affiliation: Electrical and Computer Engineering Department, University of Delaware, DE, United States.
authors.forename: Rutao
authors.initials: R
authors.lastname: Luo
authors.affiliation: Electrical Engineering Department, Pennsylvania State University, PA, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Piovoso
authors.affiliation: Electrical and Computer Engineering Department, University of Delaware, DE, United States. Electronic address: ryanz@udel.edu.
authors.forename: Ryan
authors.initials: R
authors.lastname: Zurakowski
mesh_terms: D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D023241:Antiretroviral Therapy, Highly Active; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D016325:HIV Long Terminal Repeat / Q000187:drug effects*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology; D006801:Humans; D008198:Lymph Nodes / Q000821:virology; D008954:Models, Biological; D009010:Monte Carlo Method; D011760:Pyrrolidinones / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000068898:Raltegravir Potassium; D019562:Viral Load; D014766:Viremia / Q000188:drug therapy / Q000821:virology*; D014779:Virus Replication / Q000187:drug effects / Q000235:genetics
chemical_list: D019380:Anti-HIV Agents; D011760:Pyrrolidinones; D000068898:Raltegravir Potassium
keywords: Cryptic viremia; Drug sanctuary; HIV; Mathematical biology