Coevolutionary immune system dynamics driving pathogen speciation

We introduce and analyze a within-host dynamical model of the coevolution between rapidly mutating pathogens and the adaptive immune response. Pathogen mutation and a homeostatic constraint on lymphocytes both play a role in allowing the development of chronic infection, rather than quick pathogen clearance. The dynamics of these chronic infections display emergent structure, including branching patterns corresponding to asexual pathogen speciation, which is fundamentally driven by the coevolutionary interaction. Over time, continued branching creates an increasingly fragile immune system, and leads to the eventual catastrophic loss of immune control.Comment: main article: 16 pages, 5 figures; supporting information: 3 page

The Role of Recombination for the Coevolutionary Dynamics of HIV and the Immune Response

The evolutionary implications of recombination in HIV remain not fully understood. A plausible effect could be an enhancement of immune escape from cytotoxic T lymphocytes (CTLs). In order to test this hypothesis, we constructed a population dynamic model of immune escape in HIV and examined the viral-immune dynamics with and without recombination. Our model shows that recombination (i) increases the genetic diversity of the viral population, (ii) accelerates the emergence of escape mutations with and without compensatory mutations, and (iii) accelerates the acquisition of immune escape mutations in the early stage of viral infection. We see a particularly strong impact of recombination in systems with broad, non-immunodominant CTL responses. Overall, our study argues for the importance of recombination in HIV in allowing the virus to adapt to changing selective pressures as imposed by the immune system and shows that the effect of recombination depends on the immunodominance pattern of effector T cell responses

An integrated modelling approach for R5-X4 mutation and HAART therapy assessment

We have modelled the within-patient evolutionary process during HIV infection using different methodologies. New viral strains arise during the course of HIV infection. These multiple strains of the virus are able to use different coreceptors, in particular the CCR5 and the CXCR4 (R5 and X4 phenotypes, respectively)influence the progression of the disease to the AIDS phase. We present a model of HIV early infection and CTLs response which describes the dynamics of R5 quasispecies, specifying the R5 to X4 switch and effects of immune response. We illustrate dynamics of HIV multiple strains in the presence of multidrug HAART therapy. The HAART combined with X4 strain blocker drugs might help to reduce infectivity and lead to slower progression of disease. On the methodology side, our model represents a paradigm of integrating formal methods and mathematical models as a general framework to study HIV multiple strains during disease progression, and will inch towards providing help in selecting among vaccines and drug therapies. The results presented here are one of the rare cases of methodological cross comparison (stochastic and deterministic) and a novel implementation of model checking in therapy validation

HIV/Aids - in vivo model with the roles of CTL immune cells and antiretroviral theraphy

In this work, we formulated a mathematical model to study the interaction between HIV/AIDS and Cluster of Differentiation 4 cells (CD4+T), incorporating the roles of Cytotoxic T- lymphocytes (CTLs) cells and antiretroviral therapy. The proliferation of CD4+T cells was considered to follow the logistic growth pattern. The presence of HIV in the CD4+T cells stimulates the recruitment of CD4+T and CTL cells. The recruitment of uninfected CD4+T and CTL immune cells fall purely as an exponential function of time in the presence of HIV. The basic reproduction number (R0) was obtained using the next generation matrix method. We adopted the Jacobian stability criterion and the Lyaponuv second method of stability to establish the local and global stabilities of the equilibrium states and show that HIV can be eliminated from CD4+T cells when R0 ≤ 1 but will continue to persist within CD4+T cells when R0 >1. Early medication therapy was observed to reduce viral load and increase the number of CTL cells, while CD4+T cells is kept above the AIDS bar. A high initial viral load was noticed to induce rapid decline in the number of CD4+T cells. To keep a healthy system, we recommended that the CTL and uninfected CD4+T cells population should be maintained by reducing viral load through early medication therapy and cloning of CTL cells within infected human, which fights and kills infected cells.Keywords: Basic Reproduction Number (R0), Virus-free Equilibrium (VFE), Endemic Equilibrium (EE), Locally Asymptotically Stable (LAS) and Globally Asymptotically Stable (GAS

High Epitope Expression Levels Increase Competition between T Cells

Both theoretical predictions and experimental findings suggest that T cell populations can compete with each other. There is some debate on whether T cells compete for aspecific stimuli, such as access to the surface on antigen-presenting cells (APCs) or for specific stimuli, such as their cognate epitope ligand. We have developed an individual-based computer simulation model to study T cell competition. Our model shows that the expression level of foreign epitopes per APC determines whether T cell competition is mainly for specific or aspecific stimuli. Under low epitope expression, competition is mainly for the specific epitope stimuli, and, hence, different epitope-specific T cell populations coexist readily. However, if epitope expression levels are high, aspecific competition becomes more important. Such between-specificity competition can lead to competitive exclusion between different epitope-specific T cell populations. Our model allows us to delineate the circumstances that facilitate coexistence of T cells of different epitope specificity. Understanding mechanisms of T cell coexistence has important practical implications for immune therapies that require a broad immune response

Exosomes: Versatile Nano Mediators of Immune Regulation.

One of many types of extracellular vesicles (EVs), exosomes are nanovesicle structures that are released by almost all living cells that can perform a wide range of critical biological functions. Exosomes play important roles in both normal and pathological conditions by regulating cell-cell communication in cancer, angiogenesis, cellular differentiation, osteogenesis, and inflammation. Exosomes are stable in vivo and they can regulate biological processes by transferring lipids, proteins, nucleic acids, and even entire signaling pathways through the circulation to cells at distal sites. Recent advances in the identification, production, and purification of exosomes have created opportunities to exploit these structures as novel drug delivery systems, modulators of cell signaling, mediators of antigen presentation, as well as biological targeting agents and diagnostic tools in cancer therapy. This review will examine the functions of immunocyte-derived exosomes and their roles in the immune response under physiological and pathological conditions. The use of immunocyte exosomes in immunotherapy and vaccine development is discussed