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Biomedical subjects

M A Nowak

Publications and source records attributed to M A Nowak.

At least 109 records · Page 6Linked to original sources
PubMed1996

The dynamics of hepatitis B virus infection.

We consider a cellular model of infection by the hepatitis B virus and describe how it may be used to account for two important features of the disease, namely (i) the wide variety of manifestations of infection and the age dependence thereof, and (ii) the typically long delay before the development of virus-induced liver cancer (primary hepatocellular carcinoma). The model is based on the assumption that the liver is comprised of both immature and mature hepatocytes, with these two subpopulations of cells responding contrastingly upon infection by the virus.

Animals↗
PubMed1996

Viral dynamics in hepatitis B virus infection.

Treatment of chronic hepatitis B virus (HBV) infections with the reverse transcriptase inhibitor lamivudine leads to a rapid decline in plasma viremia and provides estimates for crucial kinetic constants of HBV replication. We find that in persistently infected patients, HBV particles are cleared from the plasma with a half-life of approximately 1.0 day, which implies a 50% daily turnover of the free virus population. Total viral release into the periphery is approximately 10(11) virus particles per day. Although we have no direct measurement of the infected cell mass, we can estimate the turnover rate of these cells in two ways: (i) by comparing the rate of viral production before and after therapy or (ii) from the decline of hepatitis B antigen during treatment. These two independent methods give equivalent results: we find a wide distribution of half-lives for virus-producing cells, ranging from 10 to 100 days in different patients, which may reflect differences in rates of lysis of infected cells by immune responses. Our analysis provides a quantitative understanding of HBV replication dynamics in vivo and has implications for the optimal timing of drug treatment and immunotherapy in chronic HBV infection. This study also represents a comparison for recent findings on the dynamics of human immunodeficiency virus (HIV) infection. The total daily production of plasma virus is, on average, higher in chronic HBV carriers than in HIV-infected patients, but the half-life of virus-producing cells is much shorter in HIV. Most strikingly, there is no indication of drug resistance in HBV-infected patients treated for up to 24 weeks.

Alanine Transaminase↗
PubMed1996

Population dynamics of immune responses to persistent viruses.

Mathematical models, which are based on a firm understanding of biological interactions, can provide nonintuitive insights into the dynamics of host responses to infectious agents and can suggest new avenues for experimentation. Here, a simple mathematical approach is developed to explore the relation between antiviral immune responses, virus load, and virus diversity. The model results are compared to data on cytotoxic T cell responses and viral diversity in infections with the human T cell leukemia virus (HTLV-1) and the human immunodeficiency virus (HIV-1).

Antibodies, Viral↗
PubMed1996

Antigenic variation and the within-host dynamics of parasites.

Many parasites exhibit antigenic variation within their hosts. We use mathematical models to investigate the dynamical interaction between an antigenically varying parasite and the host's immune system. The models incorporate antigenic variation in the parasite population and the generation of immune responses directed against (i) antigens specific to individual parasite variants and (ii) antigens common to all the parasite variants. Analysis of the models allows us to evaluate the relative importance of variant-specific and cross-reactive immune responses in controlling the parasite. Early in the course of infection within the host, when parasite diversity is below a defined threshold value (the value is determined by the biological properties of the parasite and of the host's immune response), the variant-specific immune responses are predominant. Later, when the parasite diversity is high, the cross-reactive immune response is largely responsible for controlling the parasitemia. It is argued that increasing antigenic diversity leads to a switch from variant-specific to cross-reactive immune responses. These simple models mimic various features of observed infections recorded in the experimental literature, including an initial peak in parasitemia, a long and variable duration of infection with fluctuating parasitemia that ends with either the clearance of the parasite or persistent infection.

Animals↗
PubMed1995

Coinfection and the evolution of parasite virulence.

Analyses of the selection pressures acting on parasite virulence are made more complicated when individual hosts can simultaneously harbour many different strains or genotypes of a parasite. Here we explore the evolutionary dynamics of host-parasite associations in which individual hosts can be coinfected with many different parasite strains. (We take coinfection to mean that each strain transmits at a rate unaffected by the presence of others in the same host.) This study thus represents the opposite extreme to our earlier work on superinfection in which there is a dominance hierarchy such that only the most virulent strain present in a host is transmitted. For highly diverse populations of parasite strains, we find that such coinfection leads to selection for strains whose virulence-levels lie in a relatively narrow band close to the maximum consistent with the parasite's basic preproductive ratio, R0, exceeding unity.

Animals↗
PubMed1995

Immune responses against multiple epitopes.

The current understanding of antigenic escape dynamics is based on models with single epitopes. The usual idea is that a mutation which enables a pathogen (virus, bacteria, etc) to escape from a given immune response confers a selective advantage. The "escape mutant" may then increase in abundance until it induces a new specific response against itself. In this paper a new picture is developed, based on mathematical models of immune responses against several epitopes; the simplest such models can have very complicated dynamics, with some surprising features. The emergence of an escape mutant can shift the immunodominant response to another epitope. Even in the absence of mutations, antigenic oscillation is found, with distinct peaks of different virus variants and fluctuations in the size and specificity of the immune responses. The model also provides a general theory for immunodominance in the presence of antigenic variation. Immunodominance is determined by the immunogenicity and by the antigenic diversity of the competing epitopes. Antigenic oscillations and fluctuations in the cytotoxic T-lymphocyte response have been observed in infections with the human immunodeficiency virus (HIV). Shifting the immune responses to weaker epitopes can represent a mechanism for disease progression based on evolutionary dynamics and antigenic diversity of the virus.

Antigenic Variation↗
PubMed1995

The population dynamics of vertically and horizontally transmitted parasites.

We analyse a model of the transmission dynamics of a parasite transmitted both vertically and horizontally. The basic reproductive ratio (R0) of the parasite is shown to be a sum of horizontal and vertical components. We derive expressions for the equilibrium prevalence of infection for a mixture of horizontal and vertical transmission; prevalence can reach 100% if transmission is sufficiently high. At the endemic equilibrium, if prevalence is high, most transmission will in general be vertical, but horizontal transmission rates must be high to reach and stably maintain such an equilibrium. Surprisingly, for such parasites the highest equilibrium rates of vertical transmission are observed when horizontal transmission is very effective. We discuss the implications for assessing the importance of horizontal v. vertical transmission from field data, and we suggest some implications for the evolution of virulence.

Animals↗
PubMed1995

The evolution of virulence in sexually transmitted HIV/AIDS.

A mathematical model is used to examine the effects of host population demography and transmission behavior on the evolution of virulence of a sexually transmitted pathogen such as HIV. The effect of the rate at which hosts acquire new partners is shown to depend critically on the details of the host population's growth pattern, sexual contact rate, and level of infection. At density-limited equilibrium, new partner acquisition rates have no effect on virulence. In an exponentially growing host population, higher partner acquisition rates favor the less virulent strain, as do lower rates of host population growth. In contrast, in uninfected populations, faster new partner acquisition rates encourage epidemics of the more virulent strain. Two extensions of the model--one including vertical transmission and another including within-host evolution--confirm the robustness of the predictions.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Antigenic oscillations and shifting immunodominance in HIV-1 infections.

A typical protein antigen contains several epitopes that can be recognized by cytotoxic T lymphocytes (CTL), but in a characteristic antiviral immune response in vivo, CTL recognize only a small number of these potential epitopes, sometimes only one, this phenomenon is known as immunodominance. Antigenic variation within CTL epitopes has been demonstrated for the human immunodeficiency virus HIV-1 (ref. 11) and other viruses and such 'antigenic escape' may be responsible for viral persistence. Here we develop a new mathematical model that deals with the interaction between CTL and multiple epitopes of a genetically variable pathogen, and show that the nonlinear competition among CTL responses against different epitopes can explain immunodominance. This model suggests that an antigenically homogeneous pathogen population tends to induce a dominant response against a single epitope, whereas a heterogeneous pathogen population can stimulate complicated fluctuating responses against multiple epitopes. Antigenic variation in the immunodominant epitope can shift responses to weaker epitopes and thereby reduce immunological control of the pathogen population. These ideas are consistent with detailed longitudinal studies of CTL responses in HIV-1 infected patients. For vaccine design, the model suggests that the major response should be directed against conserved epitopes even if they are subdominant.

Amino Acid Sequence↗
PubMed1995

Viral dynamics in human immunodeficiency virus type 1 infection.

The dynamics of HIV-1 replication in vivo are largely unknown yet they are critical to our understanding of disease pathogenesis. Experimental drugs that are potent inhibitors of viral replication can be used to show that the composite lifespan of plasma virus and virus-producing cells is remarkably short (half-life approximately 2 days). Almost complete replacement of wild-type virus in plasma by drug-resistant variants occurs after fourteen days, indicating that HIV-1 viraemia is sustained primarily by a dynamic process involving continuous rounds of de novo virus infection and replication and rapid cell turnover.

Antiviral Agents↗
PubMed1995

Can live attenuated virus work as post-exposure treatment?

Simple mathematical models for the competition between different virus variants in the presence of a crossreactive immune response show that, contrary to expectation, selection can favour variants that induce low viral loads. Here, Sebastian Bonhoeffer and Martin Nowak suggest that such 'competitively superior', but 'less pathogenic', mutants may be a possibility for post-exposure treatment of persistent virus infections.

AIDS Vaccines↗
PubMed1995

The arithmetics of mutual help.

Computer experiments show how cooperation rather than exploitation can dominate in the Darwinian struggle for survival.

Animals↗
PubMed1995

AIDS pathogenesis: from models to viral dynamics in patients.

The course of HIV infection usually follows a pattern in which the immune system is initially able to limit viral replication, but ultimately fails. It is proposed that disease progression is a consequence of viral replication and evolution within the host, the immune response providing the selection pressure for increasing diversity. When the number of mutants rises above a certain threshold level, the immune system can no longer downregulate all the viral variants simultaneously and symptomatic disease results. Recent studies of the dynamics and kinetics of HIV infection have indicated that 30% of the free virus population in the plasma is replenished each day, a very high turnover rate. After intervention with nevirapine, resistant virus was observed to have replaced wild-type virus in the plasma within 2-4 weeks. Even in late-stage patients, the immune system has the capacity to regenerate large numbers of CD4 cells, but this ability does not continue indefinitely. This implies that to reverse immunodeficiency the principal objective of treatment in the management of HIV infection should be inhibition of viral replication and thus prevention of lymphocyte destruction.

Acquired Immunodeficiency Syndrome↗