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Biomedical subjects

H J Bremermann

Publications and source records attributed to H J Bremermann.

At least 19 recordsLinked to original sources
PubMed1995

Mechanism of HIV persistence: implications for vaccines and therapy.

Periodic infusion of autologous HIV-antigen presenting cells (APCs), that stimulate the cytotoxic (CTL) response, while being incapable of producing virus, should lower viral burden and boost CD4+ count in HIV-seropositive individuals. Viral burden reasserts itself after antiviral therapy ceases or is interrupted for long. Therapy, therefore, would have to continue for life. These are predictions from a computer model of HIV-immune kinetics. The model equations describe the interactive kinetics of viral burden, CD4+ cell decline, neutralization of free virus by antibodies, infection of cells, and killing of infected cells by CTL. The computed trajectories of the kinetic equations reproduce the typical course of an HIV infection and the model yields several predictions that are not intuitively obvious, among them: (a) Persistence of HIV infection (failure of the immune system to clear infection) is an intrinsic property of the kinetics of the HIV-immune interaction. (b) The chronic state of infection is inherently stable, which means that the infection rebounds to the determined steady state, whenever antiviral therapy stops. (c) CTL is chronically activated, and the level correlates inversely with the avidity of neutralizing antibodies. (d) APCs have to be infused at a rate such as to boost and maintain the CTL response above the chronic level. Other therapies include CTL stimulation, via the macrophage route, by erythrocytes, into which MHC binding HIV-CTL epitope polypeptide fragments have been inserted; passive immunization, virion-trapping by CD4 analogs or CD4 expressing erythrocytes; and combination therapies with AZT, IL-2. These are also analyzed. Concerning HIV etiology, the model assumes that cells other than CD4+ cells (such as macrophages/monocytes) become infected, and contribute to the viral burden, and that infectible cells remain available even as CD4+ cells become exhausted. The model further assumes that CD4+ cells decline not only through direct killing by HIV and CTL, but by dysregulation and excess apoptosis caused by the presence of virus. The model predicts that persistence of HIV infection does not depend upon latently infected cells or escape mutants, as has been suggested.(ABSTRACT TRUNCATED AT 400 WORDS)

AIDS Vaccines↗
PubMed1995

AIDS as immune system activation. Key questions that remain.

Immune system activation is gaining attention as a central part of HIV pathogenesis. Although there is no consensus yet as to the source of the signal or the result of the signalling, this line of thinking represents a significant shift in the paradigm away from considering HIV disease like any other cytopathic viral infection. Hopefully, completion of studies focussed on this approach will lead to more complete understanding of AIDS and more effective therapies, and will at least bring to the fore some of the central unanswered questions in modern cellular immunology.

Acquired Immunodeficiency Syndrome↗
PubMed1990

The HIV cytopathic effect: potential target for therapy?

HIV kills activated infected CD4+ T cells after a burst of replication and the release of large numbers of virions. From a review of the literature on HIV regulatory genes and from preliminary mathematical models of HIV dynamics at four levels (host population epidemiology, the immune system, gene regulation within infected cells, and selection of mutants) we have arrived at the theory that in the etiology of HIV the HIV cytopathic effect may actively be caused by a viral regulatory gene product. The most likely candidate is the rev regulatory protein. Rev and the analogous rex protein from HTLV-I (human T cell leukemia virus) both have two active sites with similar function: one site locates the protein in the nucleus/nucleolus, and the other site interacts with viral mRNAs, facilitating their export from the nucleus to the cytoplasm. Rev seems to have a third functional site near the 3' end. We conjecture that this site may be responsible for the cytopathic effect. We think that rev acts on cellular genes that normally induce senescence and cell death during development, or T-cell maturation, or on terminal differentiation. We propose that mathematical and computer models of the immune system could be used to explore whether suppression of the cytopathic action of the rev protein could be of therapeutic benefit in restoring the ability of the immune system to clear HIV or at least to extend latency. We also suggest how immune deficiency disease might be created as laboratory artifact in animal populations.

CD4 Antigens↗
PubMed1990

Mathematical models of HIV infection. I. Threshold conditions for transmission and host survival.

This is the second in a series of papers modeling human immunodeficiency virus (HIV) infections at four levels: transmission, interaction with the immune system, gene regulation, and selection of mutants. In the previous paper (1) we described and presented a theory of the HIV cytopathic effect based upon the models (and a review of the literature). In this article we give mathematical equations of threshold conditions that connect infectivity, length of host survival, and frequency of acts conducive to transmission. The formula is derived not only for homogeneous populations but also for populations of an arbitrary number of subgroups with varying frequencies of risk behavior, varying rates of infection and latency periods, and varying frequencies of interaction with other groups.

Cytopathogenic Effect, Viral↗
PubMed1989

A competitive exclusion principle for pathogen virulence.

For a modified Anderson and May model of host parasite dynamics it is shown that infections of different levels of virulence die out asymptotically except those that optimize the basic reproductive rate of the causative parasite. The result holds under the assumption that infection with one strain of parasite precludes additional infections with other strains. Technically, the model includes an environmental carrying capacity for the host. A threshold condition is derived which decides whether or not the parasites persist in the host population.

Animals↗
PubMed1987

The adaptive significance of sexuality.

The theory predicts that inbred strains of mice are susceptible to tumor viruses that have escaped immune recognition. The theory implies routine evolutionary extinction of asexual species and that existing parthenogenetic species would have to have evolved recently from sexually reproducing precursors. This could be tested by determining the amount of DNA divergence between parthenogenetic and related sexually reproducing species. In mammals and birds genetic substitutions occur at comparable rates, but the AIDS virus evolves about 10 million times more rapidly. This confirms the basic imbalance of rates of evolution between microparasites and metazoan hosts, which is fundamental to the theory. The organization of most eukaryotic genes into exons and introns facilitates the generation of variety of gene products, and the molecular mechanism is similar to the mechanism that generates antibody diversity in the immune response and antigenic variation in trypanosomes. It has been proposed that noncoding 'selfish' DNA is the ultimate sexually transmitted disease. If this were the case, then asexually reproducing species would have an added advantage. An alternative hypothesis is proposed: noncoding DNA could provide insertion sites for retroviruses that would prevent them from being transcribed and replicated and thus moderate their proliferation much as absorber rods moderate proliferation of neutrons in a nuclear reactor. Flowering plants have pollen selection mechanisms that enforce heterozygosity at one or more loci. It has been proposed that analogous sperm selection mechanisms exist in mammals. Such a process would account for observation of a mysterious excess molecular divergence between different strains of inbred mice.

Adaptation, Physiological↗
PubMed1985

On the stability of polymorphic host-pathogen populations.

The stability of populations of hosts and micro-parasites is investigated where each consists of n varieties that are equal in every respect except that each strain of parasites can infect only one specific strain of hosts and none of the others. Collectively the host strains are limited by a carrying capacity and through this limitation the host populations interact with each other. Hosts are assumed to reproduce asexually or such that different strains do not mate or are not fertile if they do. When the excess death rate caused by the pathogenic parasites is sufficiently large, then the host population is regulated to an equilibrium below the carrying capacity of the environment. This polymorphic equilibrium is shown to be locally asymptotically stable. When one of the parasite strains is absent, then all the other strains die out asymptotically. However, if host resistance to all infectious strains of parasites is achieved at the cost of a lower birthrate of the resistant host strain, then, if a certain condition for the various parameters is satisfied, stable coexistence between infected and resistant hosts is possible. There are many examples where susceptibility and resistance of hosts depends upon the conformation of specific proteins that are involved in host-parasite interactions and hence upon alleles at genetic loci that code for these proteins. We propose that polymorphism in wildtype populations which has been the subject of much theorizing in mathematical genetics may be due to host-pathogen interactions. Our model suggests how a polymorphic population, once established, can remain polymorphic indefinitely.

Animals↗
PubMed1985

The adaptive significance of sexuality.

A theory of sexuality and polymorphism is proposed in which diversity at the molecular level is the adaptive response of multicellular organisms to the challenge of microparasites that have smaller genomes, shorter generation times and which can evolve more quickly than their hosts. The theory has implications for genetically homogenized crops and other cultivated plants as well as for immunology. A different function of sexuality is proposed for microorganisms that reproduce both asexually and sexually. Several possible experimental tests are discussed. Mathematical modelling techniques are outlined qualitatively and compared with game-theoretical methods which may be interpreted as simplifications of population dynamics of polymorphic host-parasite populations are referenced.

Adaptation, Physiological↗
PubMed1983

A game-theoretical model of parasite virulence.

The evolution of parasitic reproductive rates, relative infectiousness and severity of disease are considered using a game-theoretical model in which parasites compete within hosts. Each parasite's fitness is assumed to be directly proportional to the product of its reproductive rate (lambda) and the length of time (T) over which it reproduces. An increase in a parasite's reproductive rate is assumed to increase its host's disease-induced mortality rate (alpha) and consequently, through host death, to decrease T. By maximizing the total number of propagules that individuals produce with respect to their individual reproductive rates, we show that competitors within a host may be favored by natural selection to reproduce at rates below their maximum potential rates. Whether competitors behaving with such restraint can coexist at a Nash equilibrium is shown to depend on the functional form of alpha (lambda) and on the number of competitors within a host. While an individual's restraint benefits its within-host competitors through increased host longevity, the model does not invoke group selection. In the model, selection favors an individual's restraint when such behavior increases the individual's total number of propagules. Concurrent increases in the absolute and relative fitness of an individual's within-host competitors can be consequences of such individual selection.

Animals↗
PubMed1983

Parasites at the origin of life.

This paper is concerned with parasitic virus-like particles and their hosts. It is proposed that parasitism must have occurred at an early stage of evolution, soon after the first self-reproducing systems had formed. When chemical building blocks for self-reproducing systems became scarce, current theories envision that some self-reproducing systems evolved the capability to synthesize materials for self-replication from chemical precursors in the environment. It is proposed that at about the same time parasitic systems (phages) arose that replicated at the expense of host systems by diverting host materials to the replication of their own genomes. With the aid of a mathematical model we demonstrate that host and phages can coexist in a stable equilibrium, depending upon the carrying capacity of the environment. If the latter falls below a threshold, then the parasites die out. A parasite that has the capability to integrate into the host genome is replicated along with it and thus escapes extinction during periods of population bottlenecks of the host population. The presence of phages creates evolutionary pressures favoring host defenses against them. Thus, modern bacteria are able to degrade most invading DNA (through restriction enzymes). Defense capabilities require a share of the genome, thus adding to the genetic complexity of organisms.

Biological Evolution↗
PubMed1982

Computer consultation in neurology: subjective and objective evaluations of the "NEUROLOGIST" system.

NEUROLOGIST is a computer system for clinical consultation in neurology. The system's strategy is patterned after the 'localize first' paradigm of the expert neurologist. The system gives explanations of its conclusions, including drawings of neurologic lesions. It currently covers 130 diagnoses and is readily expandable. In this paper the NEUROLOGIST system is described and results of objective and subjective evaluations are presented and discussed. Directions for improvement and expansion of the present system are outlined.

Computers↗
PubMed1981

Computer assisted diagnosis and computer consultation in neurology: preliminary testing of diagnostic accuracy for the neurologist system.

The Neurologist system is a computer program for consultation in clinical neurology which employs human-like reasoning in diagnosis, covers a broad diagnostic domain, has the capacity to explain strategies and conclusions and is readily expandable. Neurologist employs the strategy of first localizing a neurologic disease, then uses these data as well as mode of disease onset, rapidly to focus on a limited number of diagnostic possibilities which are then sequentially investigated. This paper presents the results of the preliminary assessment of Neurologist's diagnostic accuracy. For a set of 30 test cases, the system's leading diagnosis was correct in 77%, and separation of correct and incorrect diagnostic hypotheses was excellent. Further evaluations of the system are in progress.

Brain Diseases↗
PubMed1979

Unlinked strands as a topological constraint on chromosomal DNA, plasmid integration, and DNA repair.

It is proposed that circular chromosomal DNA must be constrained such that the two strands are topologically unlinked. This structure can be replicated without strand breakage (nicking) by locally acting enzymes. The recently discovered form V DNA satisfies this topological constraint. The structure is likely to consist of left-handed and right-handed segments of double helix. The constraint of zero linkage has to be preserved by DNA repair, plasmid insertion and by crossing over. The argument presented in this paper is a topological one, following W.F. Pohl, that linkage is a global property that cannot be measured by locally acting enzymes. In contrast to Pohl no argument in favor of a side-by-side structure is presented. A zero linkage constraint would be hereditary and compatible with a multitude of local structures.

Chemical Phenomena↗