Kouji Harada

A Switching Memory Strategy in an Immune Network Model

As an empirical knowledge on vaccination, it is known that immune memories against viral antigens (i.e., self-reproductive antigens) are sustained for a very long period more than 10 years, whereas against non-viral antigens, they are sustained only for a relatively short period less than a few years. This fact suggests that an immune system switches adaptability its memory strategy according to degree of antigen’s self-reproductive rate, its hazard rate. Therefore it is an interesting knowledge though, so far, a theory that indicates a causal relationship between durability of an immune memory and an antigen’s viral/non-viral character has not been clarified.

Self-destruction Dynamics of HIV-1 Quasi-species Population in the Presence of Mutagenic Activities☆

Abstract The present study aims to establish fundamental theories for an alternative AIDS treatment for cART based on the use of multiple anti-HIV drugs. It is well known that HIV-1 is frequently-mutated. The alternative AIDS treatment is an approach to drive HIV-1 quasi-species population to self-destruction by inducing excess mutations to HIV-1 RNA(+) genome. Namely this therapy uses the HIV-1s error-prone character as an underhanded way. This study proposes a novel HIV-1 mathematical model considered viral kinetic processes such as infection, replication, mutation, and mutagenic activities to control HIV-1 mutation rate. The model also considers four HIV-1 phenotypes: fast and slow in replication rate and viable and defective in infectious ability. Numerical simulations of the model show that enhancement of HIV-1 mutation rate causes an error catastrophe to HIV-1 quasi-species population. Furthermore, analyses of local asymptotic stability of the self-destruction state reveal that the alternative AIDS treatment has effectiveness in certain specific viral conditions.

A hub gene in an HIV-1 gene regulatory network is a promising target for anti-HIV-1 drugs

The existing anti-HIV-1 drugs have troublesome problems with side-effects and the development of drug resistance, etc. To avoid these problems by using our knowledge of complex network analyses, this study examines the topological conditions needed for a satisfactory anti-HIV-1 drug target, and suggests that a promising anti-HIV-1 drug target should be endowed with the features of a “hub” and a “bottleneck” in the HIV-1 proteins-intracellular agent interaction network.

Emergence of immune memory and tolerance in an asymmetric idiotype network

This study proposes an idiotype network model system adopted an “asymmetric” idiotype – anti-idiotypic interaction, and shows realizing immune tolerance as well as immune memory on a transient dynamics. To date, the immune tolerance was a problematic phenomenon for traditional idiotype network models adopted “symmetric” idiotypic interaction because they failed to reproduce it. This paper reports the proposed model succeeds in the display of the immune tolerance by considering an asymmetric anti-idiotypic interaction. Actually, a computational experiment clarifies that its establishment associates with high anti-idiotypic idiotypes population level of when antigens are re-dosed. This result indicates what the anti-idiotypic idiotype functions effectively plays a decisive role for the establishment of the immune tolerance. Lastly, this study closes at the suggestion that the asymmetric modeling is more immunologically relevant than the symmetric one which most theoreticians supported so far.

Mechanism of a Transient but Long-Lasting Immune Memory Function on a Self/Non-Self Boundary

Our previous study proposed an immune network model with evolving dynamics for antigen-specificity of a lymphocyte receptor, and obtained the following results: 1) the model revealed threshold dynamics to determine an immunological self/non-self boundary, and furthermore 2) the application of the threshold dynamics enabled an immune memory function. However, as the model equations were high- dimensional and nonlinear, the study could not explicate a mechanism for these immunological phenomena by analyzing the model equations. This study proposes a “minimal and analyzable” model that enables the reproduction of these two immunological phenomena. From analyses of isoclines of the model equations, 1) the threshold dynamics stems from the so-called excitable dynamics that are well-known in the firing dynamics of the neuron, and 2) the immune memory is realized not as a stable dynamical attractor, but as a long-lasting transient. This result indicates the possibility of a new type of immune memory different from the known dynamic attractor immune memory.

A Mathematical Study of Combined Use of Anti-HIV Drugs and a Mutagen

Abstract The multidrug therapy for acquired immunodeficiency syndrome (AIDS) is efficacious in suppressing viral load, but it is an inappropriate treatment for AIDS patients suffering from side effects of anti-human immunodeficiency virus (HIV) drugs or who have developed resistance against these drugs. To cure these patients, alternative AIDS therapy is necessary. In a previous study 1, we discussed the availability of an alternative AIDS treatment that plunges viral activities into chaos by inducing excessive mutations by mutagenic activity in the HIV RNA genome and established a theoretical basis for its successful use in treatment. However concurrently mathematical analyses revealed treatment is only successful when the virulence of a virus was relatively low. In this study, we develop a new treatment to tackle HIV that has high virus virulence by examining the combined effects of a mutagenic agent and existing anti-HIV drugs. The drugs used include a reverse transcriptase inhibitor and a protease inhibitor. We prove that a therapy combining drug treatments with a mutagen is superior for its capacity to handle HIV with high virulence and its shorter treatment duration.

A note on dynamical behaviors of a spatial game operated on intercrossed rules

The present study discusses a twist in hierarchical rules embedded in a spatial game system. In the typical spatial games, each player has its own strategy, and determines its action on the strategy; its action does not determine its strategy. On the dominance relationship between rules, the strategy is an upper-level rule against the action. This means the game has a hierarchy on rules. The present study in order to discuss a twist between rules, introduced a rule determining a players strategy from its immediate neighbors actions. This introduction results in not to decide which of a strategy and an action is placed in an upper-level. The present paper reports the results about dynamical behaviors observed in a spatial game system with a twist in its hierarchical rules.

Introduction to the Special Issue on “State-of-the-Art Sensor Technology in Japan 2012”

The combination of sensing technology with information and communication technology (ICT) could serve both as global eyes that monitor the environment for environmental issues, and as local eyes that monitor humans for aging society issues. System technology is also required to form such global and local eyes. This special issue, “State-of-the-Art Sensor Technology in Japan”, contains articles and reviews related to the monitoring of humans and the environment, and the integration of sensor systems.

Tolerance dependent on timing/amount of antigen-dose in an asymmetric idiotypic network

Physiological experiments demonstrate establishment of immunological tolerance is controlled by dose-timing and dose-amount of an antigen. My previous study reproduced the tolerance dependent on dose-timing of an antigen in a two Bcell clones network model with an “asymmetric” Bcell-Bcell interaction. This study first clarifies its mechanism using a dynamical system technique:nullcline analysis. Next, this study proposes a three Bcell clones network model with the same style of Bcell-Bcell interaction, and shows the model simulation can reproduce the tolerance dependent on dose-amount of an antigen: high and low zone tolerance. The success of this reproduction is worthy of attention. Because theoretical studies based on the traditional “symmetric” immune network modeling scheme have not been able to reproduce it well. This study would teach us the renewed recognition of “asymmetric” immune network modeling scheme.

A Theoretical Basis for an Acquired Immunodeficiency Syndrome Treatment by a Mutagenesis Approach

The multidrug therapy for Acquired ImmunoDeficiency Syndrome (AIDS) is efficacious in suppressing viral load but it is an inappropriate treatment for AIDS patients suffering from side effects of anti-Human Immunodeficiency Virus (HIV) drugs. To cure these patients, it is desirable to prepare an alternative AIDS therapy. This chapter focuses on an alternative AIDS treatment, which can destroy HIV central functions for infection and replication by creating excess mutations in the HIV RiboNucleic Acid (RNA) genome by mutagenic activity, and it establishes a theoretical basis for the treatment. To verify practical effectiveness of the alternative treatment from a mathematical viewpoint, this study proposes a novel HIV mathematical model that simulates a viral reproduction process by mutagenic activity. A numerical model simulation revealed enhancement of the HIVmutation rate by error catastrophe caused by mutagens, which led to viral eradication. Furthermore, local asymptotic stability analyses demonstrated the clinical effectiveness of the alternative treatment having effectiveness. Finally, this study examines combination effects of a mutagenic agent and existing anti-HIV drugs such as a reverse transcriptase inhibitor, a protease inhibitor.