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Biomedical subjects

M A Nowak

Publications and source records attributed to M A Nowak.

At least 37 records · Page 2Linked to original sources
PubMed2000

Language evolution and information theory.

This paper places models of language evolution within the framework of information theory. We study how signals become associated with meaning. If there is a probability of mistaking signals for each other, then evolution leads to an error limit: increasing the number of signals does not increase the fitness of a language beyond a certain limit. This error limit can be overcome by word formation: a linear increase of the word length leads to an exponential increase of the maximum fitness. We develop a general model of word formation and demonstrate the connection between the error limit and Shannon's noisy coding theorem.

Biological Evolution↗
PubMed2000

HIV-1 dynamics revisited: biphasic decay by cytotoxic T lymphocyte killing?

The biphasic decay of blood viraemia in patients being treated for human immunodeficiency virus type 1 (HIV-1) infection has been explained as the decay of two distinct populations of cells: the rapid death of productively infected cells followed by the much slower elimination of a second population the identity of which remains unknown. Here we advance an alternative explanation based on the immune response against a single population of infected cells. We show that the biphasic decay can be explained simply, without invoking multiple compartments: viral load falls quickly while cytotoxic T lymphocytes (CTL) are still abundant, and more slowly as CTL disappear. We propose a method to test this idea, and develop a framework that is readily applicable to treatment of other infections.

HIV Infections↗
PubMed2000

Competitive coexistence in antiviral immunity.

Adaptive immunity to viruses in vertebrates is mediated by two distinct but complementary branches of the immune system: the cellular response, which eliminates infected cells, and the humoral response, which eliminates infectious virus. This leads to an interesting contest, since the two responses compete, albeit indirectly, for proliferative stimuli. How can a host mount a coordinated antiviral campaign? Here we show that competition may lead to a state of "competitive coexistence" in which, counterintuitively, each branch complements the other, with clinical benefit to the host. The principle is similar to free-market economics, in which firms compete, but the consumer benefits. Experimental evidence suggests this is a useful paradigm in antiviral immunity.

Animals↗
PubMed2000

The basic reproductive ratio of a word, the maximum size of a lexicon.

Language is about words and rules. While there is some discussion to what extent rules are learned or innate, it is clear that words have to be learned. Here I construct a mathematical framework for the population dynamics of language evolution with particular emphasis on how words are propagated over generations. I define the basic reproductive ratio of word, R, and show that R > 1 is required for words to be maintained in the lexicon of a language. Assuming that the frequency distribution of words follow Zipf's law, an upper limit is obtained for the number of words in a language that relies exclusively on oral transmission.

Humans↗
PubMed2000

Adherence and drug resistance: predictions for therapy outcome.

We combine standard pharmacokinetics with an established model of viral replication to predict the outcome of therapy as a function of adherence to the drug regimen. We consider two types of treatment failure: failure to eliminate the wild-type virus, and the emergence of drug-resistant virus. Specifically, we determine the conditions under which resistance dominates as a result of imperfect adherence. We derive this result for both single- and triple-drug therapies, with attention to conditions which favour the emergence of viral strains that are resistant to one or more drugs in a cocktail. Our analysis provides quantitative estimates of the degree of adherence necessary to prevent resistance. We derive results specific to the treatment of human immunodeficiency virus infection, but emphasize that our method is applicable to a range of viral or other infections treated by chemotherapy.

Anti-HIV Agents↗
PubMed2000

The evolution of syntactic communication.

Animal communication is typically non-syntactic, which means that signals refer to whole situations. Human language is syntactic, and signals consist of discrete components that have their own meanings. Syntax is a prerequisite for taking advantage of combinatorics, that is, "making infinite use of finite means. The vast expressive power of human language would be impossible without syntax, and the transition from non-syntactic to syntactic communication was an essential step in the evolution of human language. We aim to understand the evolutionary dynamics of this transition and to analyse how natural selection can guide it. Here we present a model for the population dynamics of language evolution, define the basic reproductive ratio of words and calculate the maximum size of a lexicon. Syntax allows larger repertoires and the possibility to formulate messages that have not been learned beforehand. Nevertheless, according to our model natural selection can only favour the emergence of syntax if the number of required signals exceeds a threshold value. This result might explain why only humans evolved syntactic communication and hence complex language.

Animal Communication↗
PubMed2000

A new theory of cytotoxic T-lymphocyte memory: implications for HIV treatment.

We use simple mathematical models to examine the dynamics of primary and secondary cytotoxic T-lymphocyte (CTL) responses to viral infections. In particular, we are interested in conditions required to resolve the infection and to protect the host upon secondary challenge. While protection against reinfection is only effective in a restricted set of circumstances, we find that resolution of the primary infection requires persistence of CTL precursors (GTLp), as well as a fast rate of activation of the CTLp. Since these are commonly the defining characteristics of CTL memory, we propose that CTL memory may have evolved in order to clear the virus during primary challenge. We show experimental data from lymphocytic choriomeningitis virus infection in mice, supporting our theory on CTL memory. We adapt our models to HIV and find that immune impairment during the primary phase of the infection may result in the failure to establish CTL memory which in turn leads to viral persistence. Based on our models we suggest conceptual treatment regimes which ensure establishment of CTL memory. This would allow the immune response to control HIV in the long term in the absence of continued therapy.

Animals↗
PubMed2000

Direct quantitation of rapid elimination of viral antigen-positive lymphocytes by antiviral CD8(+) T cells in vivo.

Lysis of infected cells by CD8(+) T cells is an important mechanism for the control of virus infections, but remains difficult to quantify in vivo. Here, we study the elimination kinetics of viral antigen-positive lymphocytes by antiviral CD8(+) T cells using flow cytometry and mathematical analysis. In mice acutely infected with lymphocytic choriomeningitis virus, more than 99.99 % of target cells were eliminated each day, corresponding to a half-life of 1.4 h. Even in mice exposed to virus 300 days previously, and with no ex vivo killing activity, 84 % of the target cells were eliminated per day. Unexpectedly, the elimination kinetics of antigen-positive lymphocytes was not significantly impaired in mice deficient in either perforin-, CD95 ligand- or TNF-mediated cytotoxicity. For viruses with a particular tropism for lymphocytes, such as Epstein-Barr virus or HIV, our results illustrate how effectively CD8(+) T cell-mediated elimination of target cells can potentially contribute to virus control and immunosuppression.

Animals↗
PubMed2000

CD8 memory, immunodominance, and antigenic escape.

Previous theoretical work has suggested that efficient virus control or clearance requires antigen-independent persistence of memory cytotoxic T lymphocyte precursors (CTLp), and that failure to generate such memory CTLp can result in persistent infection and eventual loss of virus control. Here we use mathematical models to investigate the relationship between virus control, the clonal composition of the CTL response and the chance of the virus to evolve antigenic escape. In the presence of efficient memory CTLp, virus is controlled at very low levels by a broad CTL response directed against multiple epitopes. In this case, antigenic escape of the virus population is expected to take a very long time. On the other hand, if the CTL response is short lived in the absence of antigen, virus replicates at higher levels and is only opposed by a narrow CTL response, characterized by an immunodominant CTL clone. In this case, antigenic escape is expected to evolve in a short period of time, resulting in progressive loss of virus control. We discuss our findings in relation to data from HIV-1-infected patients.

Epitopes↗
PubMed2000

Nash equilibria for an evolutionary language game.

We study an evolutionary language game that describes how signals become associated with meaning. In our context, a language, L, is described by two matrices: the P matrix contains the probabilities that for a speaker certain objects are associated with certain signals, while the Q matrix contains the probabilities that for a listener certain signals are associated with certain objects. We define the payoff in our evolutionary language game as the total amount of information exchanged between two individuals. We give a formal classification of all languages, L(P, Q), describing the conditions for Nash equilibria and evolutionarily stable strategies (ESS). We describe an algorithm for generating all languages that are Nash equilibria. Finally, we show that starting from any random language, there exists an evolutionary trajectory using selection and neutral drift that ends up with a strategy that is a strict Nash equilibrium (or very close to a strict Nash equilibrium).

Algorithms↗
PubMed2000

Immunological transitions in response to antigenic mutation during viral infection.

Antigenic variation is an important factor in viral persistence and disease progression. We analyze immunological changes which occur in response to antigenic mutation during chronic viral infection. Using an established model of viral and immune system dynamics, we determine which qualitative shifts in the immune response can be elicited by the appearance of a new mutant. We find that antigenic mutation can cause dramatic shifts in the magnitude and type of anti-viral immune response. For example, the appearance of a mutant can elicit a new immune response which recognizes the original viral strain. We also find that novel strains of the virus which replicate more slowly than existing viral strains are able to invade and survive, even when the immune system is capable of mounting an immune response against the mutant.

Animals↗
PubMed2000

The role of antigen-independent persistence of memory cytotoxic T lymphocytes.

We use mathematical models to analyze the role of a memory cytotoxic T lymphocyte (CTL) response in viral infections. The model predicts that antigen-independent persistence of an elevated number of precursor CTL (CTLp) does not protect the host from clinical symptoms upon re-infection. Instead, we find that antigen-independent long-term persistence of CTLp is required to clear virus infections. This mechanism also applies to infection in hosts that have never experienced the pathogen before. Requirement of antigen for the long-term maintenance of CTLp results in failure to clear the infection, even in hosts characterized by a high CTL responsiveness. We compare the CTL model to a B cell model. In keeping with experimentally established findings, B cells are efficient in protecting against re-infection, but are unlikely to clear viral infections unless the virus is cytopathic. We conclude that the role of 'memory CTLp' is different from the role of memory B cells in viral infections: antigen-independent long-term persistence of CTLp is a pre-requisite to ensure clearance of infection.

Animals↗
PubMed2000

Evolution of virulence in a heterogeneous host population.

There is a large body of theoretical studies that investigate factors that affect the evolution of virulence, that is parasite-induced host mortality. In these studies the host population is assumed to be genetically homogeneous. However, many parasites have a broad range of host types they infect, and trade-offs between the parasite virulence in different host types may exist. The aim of this paper is to study the effect of host heterogeneity on the evolution of parasite virulence. By analyzing a simple model that describes the replication of different parasite strains in a population of two different host types, we determine the optimal level of virulence in both host types and find the conditions under which strains that specialize in one host type dominate the parasite population. Furthermore, we show that intrahost evolution of the parasite during an infection may lead to stable polymorphisms and could introduce evolutionary branching in the parasite population.

Animals↗
PubMed2000

Containment of simian immunodeficiency virus infection: cellular immune responses and protection from rechallenge following transient postinoculation antiretroviral treatment.

To better understand the viral and host factors involved in the establishment of persistent productive infection by primate lentiviruses, we varied the time of initiation and duration of postinoculation antiretroviral treatment with tenofovir (9-[2-(R)-(phosphonomethoxy)propyl]adenine) while performing intensive virologic and immunologic monitoring in rhesus macaques, inoculated intravenously with simian immunodeficiency virus SIVsmE660. Postinoculation treatment did not block the initial infection, but we identified treatment regimens that prevented the establishment of persistent productive infection, as judged by the absence of measurable plasma viremia following drug discontinuation. While immune responses were heterogeneous, animals in which treatment resulted in prevention of persistent productive infection showed a higher frequency and higher levels of SIV-specific lymphocyte proliferative responses during the treatment period compared to control animals, despite the absence of either detectable plasma viremia or seroconversion. Animals protected from the initial establishment of persistent productive infection were also relatively or completely protected from subsequent homologous rechallenge. Even postinoculation treatment regimens that did not prevent establishment of persistent infection resulted in downmodulation of the level of plasma viremia following treatment cessation, compared to the viremia seen in untreated control animals, animals treated with regimens known to be ineffective, or the cumulative experience with the natural history of plasma viremia following infection with SIVsmE660. The results suggest that the host may be able to effectively control SIV infection if the initial exposure occurs under favorable conditions of low viral burden and in the absence of ongoing high level cytopathic infection of responding cells. These findings may be particularly important in relation to prospects for control of primate lentiviruses in the settings of both prophylactic and therapeutic vaccination for prevention of AIDS.

Adenine↗
PubMed2000

Generalized pruritus without primary lesions. Differential diagnosis and approach to treatment.

A 65-year-old man presented with recurrent generalized pruritus and excoriations of many years' duration. He had been treated with antihistamines, topical corticosteroids, and antibiotics for secondary wound infections, but improvement was only temporary. He had also been hospitalized for leg ulcers complicated by cellulitis. Examination revealed multiple oval and linear red papules and nodules measuring 0.5 to 2 cm in diameter. Some of the lesions were eroded and had a central crater and yellowish crust. The patient also had hypopigmented linear scars localized to the posterior scalp, neck, upper back, chest, abdomen, arms, and legs with sparing of the middle and lower back (figures 1 and 2). An ulcer measuring 1.5 x 2 cm that was surrounded by indurated skin was present on the medial aspect of his right ankle. The ulcer was partially covered by yellow exudate. There was no evidence of cellulitis. Liver enzyme, serum creatinine, and thyrotropin levels, as well as a chest roentgenogram, were normal. Wound cultures for bacteria and fungi were nonsignificant. A punch biopsy from a representative lesion showed an abrupt epidermal defect with sparse superficial lymphocytic infiltrate in the dermis. The patient was admitted to the hospital to isolate him from his home environment. He received a 10-day course of systemic cephalexin, topical clobetasol propionate ointment for the affected skin areas, and oral hydroxyzine for pruritus. Ultraviolet light therapy was instituted once daily and was to continue for 2 months. His lesions had improved moderately by the time he was discharged from the hospital. On follow-up 2 weeks later, his lesions were flat and had resulted in hypopigmented scars. Three months later, however, he had persistent, intense pruritus, and new excoriations had developed on his forearms and back. He improved after receiving treatment with oral doxepin hydrochloride.

Aged↗
PubMed1999

Virus phenotype switching and disease progression in HIV-1 infection.

One of the phenotypic distinctions between different strains of human immunodeficiency virus type 1 (HIV-1) has to do with the ability to cause target cells to form large multinucleate bodies known as syncytia. There are two phenotypes according to this characterization: syncytium-inducing (SI) and non-syncytium-inducing (NSI). NSI strains are usually present throughout infection, while SI strains are typically seen at the beginning of the infection and near the onset of AIDS. The late emergence of SI strains is referred to as phenotype switching. In this paper we analyse the factors that lead to phenotype switching and contribute to the dynamics of disease progression. We show that a strong immune system selects for NSI strains while a weak immune system favours SI strains. The model explicitly accounts for the fact that CD4+ cells are both targets of HIV infection and crucial for activating immune responses against HIV In such a model, SI strains can emerge after a long and variable period of NSI dominated infection. Furthermore, versions of the model which do not explicitly account for HIV-specific, activated CD4+ cells do not exhibit phenotype switching, emphasizing the critical importance of this pool of cells.

Computer Simulation↗
PubMed1999

Specific therapy regimes could lead to long-term immunological control of HIV.

We use mathematical models to study the relationship between HIV and the immune system during the natural course of infection and in the context of different antiviral treatment regimes. The models suggest that an efficient cytotoxic T lymphocyte (CTL) memory response is required to control the virus. We define CTL memory as long-term persistence of CTL precursors in the absence of antigen. Infection and depletion of CD4(+) T helper cells interfere with CTL memory generation, resulting in persistent viral replication and disease progression. We find that antiviral drug therapy during primary infection can enable the development of CTL memory. In chronically infected patients, specific treatment schedules, either including deliberate drug holidays or antigenic boosts of the immune system, can lead to a re-establishment of CTL memory. Whether such treatment regimes would lead to long-term immunologic control deserves investigation under carefully controlled conditions.

CD4-Positive T-Lymphocytes↗