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Biomedical subjects

M A Nowak

Publications and source records attributed to M A Nowak.

At least 91 records · Page 5Linked to original sources
PubMed1997

Evolution of genetic redundancy.

Genetic redundancy means that two or more genes are performing the same function and that inactivation of one of these genes has little or no effect on the biological phenotype. Redundancy seems to be widespread in genomes of higher organisms. Examples of apparently redundant genes come from numerous studies of developmental biology, immunology, neurobiology and the cell cycle. Yet there is a problem: genes encoding functional proteins must be under selection pressure. If a gene was truly redundant then it would not be protected against the accumulation of deleterious mutations. A widespread view is therefore that such redundancy cannot be evolutionarily stable. Here we develop a simple genetic model to analyse selection pressures acting on redundant genes. We present four cases that can explain why genetic redundancy is common. In three cases, redundancy is even evolutionarily stable. Our theory provides a framework for exploring the evolution of genetic organization.

Animals↗
PubMed1997

Virus dynamics and drug therapy.

The recent development of potent antiviral drugs not only has raised hopes for effective treatment of infections with HIV or the hepatitis B virus, but also has led to important quantitative insights into viral dynamics in vivo. Interpretation of the experimental data depends upon mathematical models that describe the nonlinear interaction between virus and host cell populations. Here we discuss the emerging understanding of virus population dynamics, the role of the immune system in limiting virus abundance, the dynamics of viral drug resistance, and the question of whether virus infection can be eliminated from individual patients by drug treatment.

Animals↗
PubMed1997

Pre-existence and emergence of drug resistance in HIV-1 infection.

Antiviral treatment of HIV-1 infection often fails because of the rapid emergence of resistant virus within weeks of the start of therapy. This raises the question of whether resistant viruses pre-exist in drug-naive patients or whether it is produced after the start of therapy. Here we compare the likelihood of pre-existence with the likelihood of production of resistant virus during therapy. We show that provided resistant virus pre-exists, then a stronger therapy may lead to a greater initial reduction of virus load, but will also cause a faster rise of resistant virus. In this case the total benefit of treatment is independent of the degree of inhibition of sensitive virus. If, on the other hand, resistant mutants do not pre-exist, then the emergence of resistance during treatment depends on the efficacy of the drug. If the drug is sufficiently potent to eradicate sensitive virus, then the probability that resistant mutants first appear during therapy is smaller than the probability that they existed before therapy. If the drug cannot eradicate the sensitive virus, then after sufficiently long time resistant mutants will appear. However, mutants that are unlikely to pre-exist may taken long time to appear.

Acquired Immunodeficiency Syndrome↗
PubMed1997

The logic of contrition.

A highly successful strategy for the Repeated Prisoner's Dilemma is Contrite Tit For Tat, which bases its decisions on the "standings" of the two players. This strategy is as good as Tit For Tat at invading populations of defectors, and much better at overcoming errors in implementation against players who are also using it. However, it is vulnerable to errors in perception. In this paper, we discuss the merits of Contrite Tit For Tat and compare it with other strategies, like Pavlov and the newly-introduced Remorse. We embed these strategies into an eight-dimensional space of stochastic strategies which we investigate by analytical means and numerical simulations. Finally, we show that if one replaces the conventions concerning the "standing" by other, even simpler conventions, one obtains an evolutionarily stable strategy (called Prudent Pavlov) which is immune against both mis-perception and mis-implementation.

Animals↗
PubMed1997

Dynamic multidrug therapies for HIV: a control theoretic approach.

Motivated by the inability of current drug treatment to provide long-term benefit to HIV-infected individuals, we derive HIV therapeutic strategies by formulating and analyzing a mathematical control problem. The model tracks the dynamics of uninfected and infected CD4+ cells and free plasma virus, and allows the virus to mutate into various strains. At each point in time, several different therapeutic options are available, where each option corresponds to a combination of reverse transcriptase inhibitors. The controller observes the individual's current status and chooses among the therapeutic options in a dynamic fashion in order to minimize the total viral load. Our initial numerical results suggest that dynamic therapies have the potential to significantly outperform the static protocols that are currently in use; by anticipating and responding to the disease progression, the dynamic strategy reduces the total free virus, increases the uninfected CD4+ count, and delays the emergence of drug-resistant strains.

CD4-Positive T-Lymphocytes↗
PubMed1997

Anti-viral drug treatment: dynamics of resistance in free virus and infected cell populations.

Anti-viral drug treatment of infections with the human immunodeficiency virus type I (HIV-1) usually leads to a rapid decline in the abundance of plasma virus. The effect of single drug therapy, however, is often only short-lived as the virus readily develops drug-resistant mutants. In this paper we provide analytic approximations for the rate of emergence of resistant virus. We study the decline of wildtype virus and the rise of resistant mutant virus in different compartments of the virus population such as free plasma virus, cells infected with actively replicating virus, long-lived infected cells and cells carrying defective provirus. The model results are compared with data on the rise of drug-resistant virus in three HIV-1 infected patients treated with neverapine (NVP). We find that the half-life of latently infected cells is between 10 and 20 days, whereas the half-life of cells with defective provirus is about 80 days. We also provide a crude estimate for the basic reproductive ratio of HIV-1 during NVP therapy.

Antiviral Agents↗
PubMed1997

Antigenic diversity thresholds and hazard functions.

In this paper, we answer some points made in a recent paper by N.I. Stilianakis and coworkers on the antigenic diversity threshold model for acquired immune deficiency syndrome pathogenesis. An extended version of the model is then used to compute hazard functions for the human immunodeficiency virus incubation period that are in agreement with empirically observed hazard functions.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Virus load and antigenic diversity.

In this paper, we analyse mathematical models for the interaction between virus replication and immune responses. We show that the immune system can provide selection pressure for or against viral diversity. The paper provides new insights into the relationship between virus load (=the abundance of virus in an infected individual) and antigenic diversity. Antigenic variation can increase virus load during infections, but the correlation between load and diversity in comparisons among different infected individuals can be positive or negative, depending on whether individuals differ in their cross-reactive or strain-specific immune responses. We derive two models: our first model applies to any replicating parasite that can escape from immune responses; our second model includes immune function impairment, and specifically describes infections with the human immunodeficiency virus (HIV).

Antigenic Variation↗
PubMed1997

Evolutionary origins and maintenance of redundant gene expression during metazoan development.

Various levels of redundancy in developmental gene function appear common in complex metazoans. There might be no apparent phenotype at many, or even any, of a gene's specific expression sites in homozygous null mutant embryos. Here we ask what underlies the origin of such arrangements. The generation of families of genes by duplication has clearly been important. Additionally, however, selection might have driven molecularly unrelated genes, which encode proteins of similar physiological function, to become expressed during the same sets of developmental events (times and places), even though each such gene might initially have evolved in connection with just one of these events.

Animals↗
PubMed1997

Late escape from an immunodominant cytotoxic T-lymphocyte response associated with progression to AIDS.

The precise role played by HIV-specific cytotoxic T lymphocytes (CTL) in HIV infection remains controversial. Despite strong CTL responses being generated during the asymptomatic phase, the virus persists and AIDS ultimately develops. It has been argued that the virus is so variable, and the virus turnover so great that escape from CTL recognition would occur continually, but so far there is limited evidence for CTL escape. The opposing argument is that evidence for CTL escape is present but hard to find because multiple anti-HIV immune responses are acting simultaneously during the asymptomatic phase of infection. We describe six donors who make a strong CTL response to an immunodominant HLA-B27-restricted epitope. In the two donors who progressed to AIDS, CTL escape to fixation by the same mutation was observed, but only after 9-12 years of epitope stability. CTL escape may play an important role in the pathogenesis of HIV infection.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Viral dynamics of primary viremia and antiretroviral therapy in simian immunodeficiency virus infection.

Mathematical modeling of viral replication dynamics, based on sequential measurements of levels of virion-associated RNA in plasma during antiretroviral treatment, has led to fundamental new insights into human immunodeficiency virus type 1 pathogenesis. We took advantage of the simian immunodeficiency virus (SIV)-infected macaque model to perform detailed measurements and mathematical modeling during primary infection and during treatment of established infection with the antiretroviral drug (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA). The calculated clearance half-life for productively infected cells during resolution of the peak viremia of primary infection was on the order of 1 day, with slightly shorter clearance half-lives calculated during PMPA treatment. Viral reproduction rates upon discontinuation of PMPA treatment after 2 weeks were approximately twofold greater than those obtained just prior to initiation of treatment in the same animals, likely reflecting accumulation of susceptible target cells during treatment. The basic reproductive ratio (R0) for the spread of SIV infection in vivo, which represents the number of productively infected cells derived from each productively infected cell at the beginning of infection, was also estimated. This parameter quantifies the extent to which antiviral therapy or vaccination must limit the initial spread of virus to prevent establishment of chronic disseminated infection. The results thus provide an important guide for efforts to develop vaccines against SIV and, by extension, human immunodeficiency virus.

AIDS Vaccines↗
PubMed1997

The extent of early viral replication is a critical determinant of the natural history of simian immunodeficiency virus infection.

Different patterns of viral replication correlate with the natural history of disease progression in humans and macaques infected with human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV), respectively. However, the viral and host factors influencing these patterns of viral replication in vivo are poorly understood. We intensively studied viral replication in macaques receiving identical inocula of SIV. Marked differences in viral replication patterns were apparent within the first week following inoculation, a time prior to the development of measurable specific immune effector responses to viral antigens. Plasma viral RNA levels measured on day 7 postinoculation correlated with levels measured in the postacute phase of infection. Differences in the susceptibility of host cells from different animals to in vitro SIV infection correlated with the permissiveness of the animals for early in vivo viral replication and hence with the postacute set point level of plasma viremia. These results suggest that host factors that exert their effects prior to full development of specific immune responses are critical in establishing the in vivo viral replication pattern and associated clinical course in subjects infected with SIV and, by extension, with HIV-1.

Animals↗
PubMed1997

Human immunodeficiency virus drug therapy and virus load.

Analysis of the short-term dynamics of human immunodeficiency virus (HIV) type 1 infection in response to drug therapy has elucidated crucial kinetic properties of viral dynamics in vivo (D. D. Ho et al., Nature 373:123-126, 1995; A. S. Perelson et al., Science 271:1582-1586, 1996; X. Wei et al., Nature 373:117-122, 1995). Here we investigated long-term changes in virus load in patients treated with a combination of lamivudine and zidovudine to identify principal factors responsible for the observed 10- to 100-fold sustained suppression of virus load in vivo. Interestingly, most standard accounts of virus dynamics cannot explain a large sustained reduction without shifting the virus very close to extinction. The effect can be explained by taking into consideration either (i) the immune response against HIV, (ii) the killing of uninfected CD4 cells, or (iii) the differential efficacies of the drugs in different cell populations.

Anti-HIV Agents↗
PubMed1996

Cytotoxic T lymphocytes and viral turnover in HIV type 1 infection.

To understand the role of the immune system in limiting HIV type 1 replication, it is critical to know to what extent the rapid turnover of productively infected cells is caused by viral cytopathicity or by immune-mediated lysis. We show that uncultured peripheral blood mononuclear cells of many patients contain cytotoxic T lymphocytes (CTL) that lyse target cells-at plausible peripheral blood mononuclear cell-to-target ratios-with half-lives of less than 1 day. In 23 patients with CD4 counts ranging from 10 to 900 per microliter, the average rate of CTL-mediated lysis corresponds to a target cell half-life of 0.7 day. We develop mathematical models to calculate the turnover rate of infected cells subjected to immune-mediated lysis and viral cytopathicity and to estimate the fraction of cells that are killed by CTL as opposed to virus. The models provide new interpretations of drug treatment dynamics and explain why the observed rate of virus decline is roughly constant for different patients. We conclude that in HIV type 1 infection, CTL-mediated lysis can reduce virus load by limiting virus production, with small effects on the half-life of infected cells.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Viral dynamics in vivo: limitations on estimates of intracellular delay and virus decay.

Anti-viral drug treatment of human immunodeficiency virus type I (HIV-1) and hepatitis B virus (HBV) infections causes rapid reduction in plasma virus load. Viral decline occurs in several phases and provides information on important kinetic constants of virus replication in vivo and pharmacodynamical properties. We develop a mathematical model that takes into account the intracellular phase of the viral life-cycle, defined as the time between infection of a cell and production of new virus particles. We derive analytic solutions for the dynamics following treatment with reverse transcriptase inhibitors, protease inhibitors, or a combination of both. For HIV-1, our results show that the phase of rapid decay in plasma virus (days 2-7) allows precise estimates for the turnover rate of productively infected cells. The initial quasi-stationary phase (days 0-1) and the transition phase (days 1-2) are explained by the combined effects of pharmacological and intracellular delays, the clearance of free virus particles, and the decay of infected cells. Reliable estimates of the first three quantities are not possible from data on virus load only; such estimates require additional measurements. In contrast with HIV-1, for HBV our model predicts that frequent early sampling of plasma virus will lead to reliable estimates of the free virus half-life and the pharmacological properties of the administered drug. On the other hand, for HBV the half-life of infected cells cannot be estimated from plasma virus decay.

Acquired Immunodeficiency Syndrome↗