Papers by James Cavenaugh
Bulletin of Mathematical …, Jan 1, 2008
Growth competition assays have been developed to quantify the relative fitness of HIV-1 mutants. ... more Growth competition assays have been developed to quantify the relative fitness of HIV-1 mutants. In this article, we develop mathematical models to describe viral/cellular dynamic interactions in the assay system from which the competitive fitness indices or parameters are defined. In our previous HIV-viral fitness experiments, the concentration of uninfected target cells was assumed to be constant (Wu et al. 2006). But this may not be true in some experiments. In addition, dual infection may frequently occur in viral fitness experiments and may not be ignorable. Here, we relax these two assumptions and extend our earlier viral fitness model (Wu et al. 2006). The resulting models then become nonlinear ODE systems for which closed-form solutions are not achievable. In the new model, the viral relative fitness is a function of time since it depends on the target cell concentration. First, we studied the structure identifiability of the nonlinear ODE models. The identifiability analysis showed that all parameters in the proposed models are identifiable from the flow-cytometry-based experimental data that we collected. We then employed a global optimization approach (the differential evolution algorithm) to directly estimate the kinetic parameters as well as the relative fitness index in the nonlinear ODE models using nonlinear least square regression based on the experimental data. Practical identifiability was investigated via Monte Carlo simulations.
… on Parallel and …, Jan 1, 2009
Pharmaceutical …, Jan 1, 2003
Cytometry Part B: …, Jan 1, 2007
Pharmaceutical …, Jan 1, 2004
ABSTRACT For a peptide vaccine to be effective in generating an antibody response, it generally m... more ABSTRACT For a peptide vaccine to be effective in generating an antibody response, it generally must incorporate both B cell epitopes, against which the antibody response is to be directed, and T cell epitopes, which are responsible for stimulating helper T cells. The first part of this work is concerned with the question, "How well can a T cell epitope replace the carrier protein from which it is derived?" To answer this question two studies were done: an initial, direct comparison between a protein (the Fab' fragment of murine monoclonal anti-fluorescein antibody 9-40) coupled to hen egg lysozyme (HEL) and the same protein coupled to the immunodominant T cell epitope from HEL for BIO.A (H-2a) mice, along with negative controls, and a second, dose response study with fluorescein (FL) as the B cell epitope attached to a multiple antigenic peptide (MAP) version of this T cell epitope, along with positive and negative controls (HEL and a MAP in which the epitope sequence was replaced by glycine residues, respectively). This study showed a half-sigmoidal curve for the FL-(T epitope) immunogen, no response to the negative control except at the highest dose used, and a fairly constant and high response for both the experimental MAP and the fluoresceinated HEL. The initial study described above gave a very specific anti-idiotype response for the (9-40)Fab'-HEL construct. Another, follow-up study comparing a peptide mimic based on an important idiotope, the third complementarity determining region of the heavy chain (the CDR-H3 loop), to the intact idiotype was also conducted. In this study the peptide mimic of the CDR-H3 loop was the B cell epitope; it was also coupled to HEL. The question being addressed was, "How well can an idiotope peptide mimic replace its parent idiotype?" B10.A mice were immunized with (B epitope)-HEL, (9-40)Fab'-HEL, (B epitope) + HEL mixed together, or just the B epitope. The essential issue was crossreactivity, and this was observed to increase with succeeding immunizations. Molecular dynamics simulations with generalized Born implicit solvation or particle mesh Ewald electrostatics were also used to provide insight into the structural basis of idiotopic phenomena. Doctor of Philosophy; NSF Grant #CDA9601580, IBM's SUR grant to the Universtiy of Utah, SGI Supercomputing Visualization Center Grant, University of Utah Interdisciplinary Program in Biological Chemistry, from the Center for Biopolymers at Interfaces (CBI)/National Institues of Health (NIH) Training Grant (GM 08393), from a University of Utah Research Grant, from a Pharmaceutical Research and Manufactures of American (PhRMA) Predoctroal Fellowsihp, and from a CBI Seed Grant.
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Papers by James Cavenaugh