Luca Sguanci

Modeling HIV quasispecies evolutionary dynamics

BackgroundDuring the HIV infection several quasispecies of the virus arise, which are able to use different coreceptors, in particular the CCR5 and CXCR4 coreceptors (R5 and X4 phenotypes, respectively). The switch in coreceptor usage has been correlated with a faster progression of the disease to the AIDS phase. As several pharmaceutical companies are starting large phase III trials for R5 and X4 drugs, models are needed to predict the co-evolutionary and competitive dynamics of virus strains.ResultsWe present a model of HIV early infection which describes the dynamics of R5 quasispecies and a model of HIV late infection which describes the R5 to X4 switch. We report the following findings: after superinfection (multiple infections at different times) or coinfection (simultaneous infection by different strains), quasispecies dynamics has time scales of several months and becomes even slower at low number of CD4+ T cells. Phylogenetic inference of chemokine receptors suggests that viral mutational pathway may generate a large variety of R5 variants able to interact with chemokine receptors different from CXCR4. The decrease of CD4+ T cells, during AIDS late stage, can be described taking into account the X4-related Tumor Necrosis Factor dynamics.ConclusionThe results of this study bridge the gap between the within-patient and the inter-patients (i.e. world-wide) evolutionary processes during HIV infection and may represent a framework relevant for modeling vaccination and therapy.

Modeling viral coevolution: HIV multi-clonal persistence and competition dynamics

The coexistence of different viral strains (quasispecies) within the same host are nowadays observed for a growing number of viruses, most notably HIV, Marburg and Ebola, but the conditions for the formation and survival of new strains have not yet been understood. We present a model of HIV quasispecies competition, which describes the conditions of viral quasispecies coexistence under different immune system conditions. Our model incorporates both T and B cells responses, and we show that the role of B cells is important and additive to that of T cells. Simulations of coinfection (simultaneous infection) and superinfection (delayed secondary infection) scenarios in the early stages (days) and in the late stages of the infection (years) are in agreement with emerging molecular biology findings. The immune response induces a competition among similar phenotypes, leading to differentiation (quasispeciation), escape dynamics and complex oscillations of viral strain abundance. We found that the quasispecies dynamics after superinfection or coinfection has time scales of several months and becomes even slower when the immune system response is weak. Our model represents a general framework to study the speed and distribution of HIV quasispecies during disease progression, vaccination and therapy.

The influence of risk perception in epidemics: a cellular agent model

Our work stems from the consideration that the spreading of a disease is modulated by the individuals perception of the infected neighborhood and his/her strategy to avoid being infected as well We introduced a general “cellular agent” model that accounts for a heterogeneous and variable network of connections The probability of infection is assumed to depend on the perception that an individual has about the spreading of the disease in her local neighborhood and on broadcasting media In the one-dimensional homogeneous case the model reduces to the DK one, while for long-range coupling the dynamics exhibits large fluctuations that may lead to the complete extinction of the disease.

Apparent Fractal Dimensions in the HMF Model

Abstract We show that recent observations of fractal dimensions in the μ‐space of N‐body Hamiltonian systems with long‐range interactions are due to finite N and finite resolution effects. We provide strong numerical evidence that, in the continuum (Vlasov) limit, a set which initially is not a fractal (e.g., a line in 2D) remains such for all finite times. We perform this analysis for the Hamiltonian mean field (HMF) model, which describes the motion of a system of N fully coupled rotors. The analysis can be indirectly confirmed by studying the evolution of a large set of initial points for the Chirikov standard map.

Mathematical Model of HIV Superinfection and Comparative Drug Therapy

We have modeled the within-patient evolutionary process during HIV infection. During the HIV infection several quasispecies of the virus arise. These quasispecies are able to use different coreceptors, in particular the CCR5 and CXCR4 (R5 and X4 phenotypes, respectively). The switch in coreceptor usage has been correlated with a faster progression of the disease to the AIDS phase. As several pharmaceutical companies are getting ready to start large phase III trials for their R5 blocking drugs, models are needed to predict the co-evolutionary and competitive dynamics of virus strains. Moreover, we have considered CTLs response and effect of TNF. We present a model of HIV early infection and CTLs response which describes the dynamics of R5 quasispecie and a model of HIV late infection, specifying the R5 to X4 switch and effect of immune response. We report the following findings: quasispecies dynamics after superinfection or coinfection have time scales of several months and become even slower in presence of the CTLs response. In addition, we illustrate dynamics of HIV quasispecies on HAART, Maraviroc and Zinc-finger nucleases(ZFN) therapies. Our model represents a general framework to study the mutation and distribution of HIV quasispecies during disease progression, and can be used to design vaccines and drug therapies.

Modeling evolutionary dynamics of HIV infection

We have modelled the within-patient evolutionary process during HIV infection. We have studied viral evolution at population level (competition on the same receptor) and at species level (competitions on different receptors). During the HIV infection, several mutants of the virus arise, which are able to use different chemokine receptors, in particular the CCR5 and CXCR4 coreceptors (termed R5 and X4 phenotypes, respectively). Phylogenetic inference of chemokine receptors suggests that virus mutational pathways may generate R5 variants able to interact with a wide range of chemokine receptors different from CXCR4. Using the chemokine tree topology as conceptual framework for HIV viral speciation, we present a model of viral phenotypic mutations from R5 to X4 strains which reflect HIV late infection dynamics. Our model investigates the action of Tumor Necrosis Factor in AIDS progression and makes suggestions on better design of HAART therapy.

A cellular automata model for ripple dynamics

We present a simple cellular automata model to address the issue of aeolian ripple formation and evolution Our simplified approach accounts for the basic physical mechanisms and enables to reproduce the observed phenomenology in the framework of a near-equilibrium statistical mechanics formulation.