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Biomedical subjects

Sebastian Bonhoeffer

Publications and source records attributed to Sebastian Bonhoeffer.

44 records · Page 3Linked to original sources
PubMed2003

Human immunodeficiency virus type 1 fitness is a determining factor in viral rebound and set point in chronic infection.

Human immunodeficiency virus type 1 (HIV-1) isolates from 20 chronically infected patients who participated in a structured treatment interruption (STI) trial were studied to determine whether viral fitness influences reestablishment of viremia. Viruses derived from individuals who spontaneously controlled viremia had significantly lower in vitro replication capacities than viruses derived from individuals that did not control viremia after interruption of antiretroviral therapy (ART), and replication capacities correlated with pre-ART and post-STI viral set points. Of note, no clinically relevant improvement of viral loads upon STI occurred. Virus isolates from controlling and noncontrolling patients were indistinguishable in terms of coreceptor usage, genetic subtype, and sensitivity to neutralizing antibodies. In contrast, viruses from controlling patients exhibited increased sensitivity to inhibition by chemokines. Sensitivity to inhibition by RANTES correlated strongly with slower replication kinetics of the virus isolates, suggesting a marked dependency of these virus isolates on high coreceptor densities on the target cells. In summary, our data indicate that viral fitness is a driving factor in determining the magnitude of viral rebound and viral set point in chronic HIV-1 infection, and thus fitness should be considered as a parameter influencing the outcome of therapeutic intervention in chronic infection.

Adult↗
PubMed2002

Procedures for reliable estimation of viral fitness from time-series data.

In order to develop a better understanding of the evolutionary dynamics of HIV drug resistance, it is necessary to quantify accurately the in vivo fitness costs of resistance mutations. However, the reliable estimation of such fitness costs is riddled with both theoretical and experimental difficulties. Experimental fitness assays typically suffer from the shortcoming that they are based on in vitro data. Fitness estimates based on the mathematical analysis of in vivo data, however, are often questionable because the underlying assumptions are not fulfilled. In particular, the assumption that the replication rate of the virus population is constant in time is frequently grossly violated. By extending recent work of Marée and colleagues, we present here a new approach that corrects for time-dependent viral replication in time-series data for growth competition of mutants. This approach allows a reliable estimation of the relative replicative capacity (with confidence intervals) of two competing virus variants growing within the same patient, using longitudinal data for the total plasma virus load, the relative frequency of the two variants and the death rate of infected cells. We assess the accuracy of our method using computer-generated data. An implementation of the developed method is freely accessible on the Web (http://www.eco.ethz.ch/fitness.html).

Anti-HIV Agents↗
PubMed2002

HIV coreceptor usage and drug treatment.

The human immunodeficiency virus (HIV) infects a wide range of human cells. Cell entry is mediated through the CD4 receptor and a variety of coreceptors, most importantly the chemokine receptors CCR5 and CXCR4. Some antiretroviral agents selectively inhibit different HIV phenotypes depending on their coreceptor usage. Here, we analyse mathematical models, which describe the in vivo interaction of HIV phenotypes, differing in their coreceptor usage, with two target cell types (naive and memory CD4+ T cells). In particular, we investigate how the selection pressures on CCR5- and CXCR4-using HIV variants change as a result of treatment with coreceptor-specific antiretroviral agents. Our main result is that CXCR4 inhibitors increase the selection pressure in favor of the emergence of CCR5-using variants, thus selecting for coexistence of CXCR4- and CCR5-using variants, whereas CCR5 inhibitors increase the selection pressure against CCR5-using variants, thus selecting against coexistence. These results shed new light on the potential risks and benefits of coreceptor inhibitors.

Antiviral Agents↗
PubMed2002

Dose-dependent infection rates of parasites produce the Allee effect in epidemiology.

In many epidemiological models of microparasitic infections it is assumed that the infection process is governed by the mass-action principle, i.e. that the infection rate per host and per parasite is a constant. Furthermore, the parasite-induced host mortality (parasite virulence) and the reproduction rate of the parasite are often assumed to be independent of the infecting parasite dose. However, there is empirical evidence against those three assumptions: the infection rate per host is often found to be a sigmoidal rather than a linear function of the parasite dose to which it is exposed; and the lifespan of infected hosts as well as the reproduction rate of the parasite are often negatively correlated with the parasite dose. Here, we incorporate dose dependences into the standard modelling framework for microparasitic infections, and draw conclusions on the resulting dynamics. Our model displays an Allee effect that is characterized by an invasion threshold for the parasite. Furthermore, in contrast to standard epidemiological models a parasite strain needs to have a basic reproductive rate that is substantially greater than 1 to establish an infection. Thus, the conditions for successful invasion of the parasite are more restrictive than in mass-action infection models. The analysis further suggests that negative correlations of the parasite dose with host lifespan and the parasite reproduction rate helps the parasite to overcome the invasion constraints of the Allee-type dynamics.

Animals↗
PubMed2002

Residual viral replication during antiretroviral therapy boosts human immunodeficiency virus type 1-specific CD8+ T-cell responses in subjects treated early after infection.

Human immunodeficiency virus type 1 (HIV-1)-infected subjects treated early after infection have preserved HIV-1-specific CD4+ T-cell function. We studied the effect of highly active antiretroviral therapy (HAART) on the frequency of HIV-1-specific CD8+ T cells in patients treated during early (n = 31) or chronic (n = 23) infection. The degree of viral suppression and time of initiation of treatment influenced the magnitude of the CD8+ T-cell response. HIV-1-specific CD8+ T cells can increase in number after HAART in subjects treated early after infection who have episodes of transient viremia.

Acute Disease↗
PubMed2002

Contribution of peaks of virus load to simian immunodeficiency virus pathogenesis.

The mechanisms causing AIDS and subsequently death in human immunodeficiency virus type 1 infection are not yet fully understood. Nonetheless, correlates of accelerated progression to disease based on immunological and virological markers have been identified. The best correlate identified to date is the baseline virus load or the so-called viral set point. By focusing on a virus load measurement from a restricted time range, however, we ignore valuable information contained in the long-term profile of the virus load. Here, we investigate the relationship between virus load and survival with the aid of a statistical model. The model takes into consideration the virus load at every stage of the disease. In particular, we aim to determine the effect of peaks of virus load on disease progression. We fit our model to unique sequential viral load data of 12 simian immunodeficiency virus mac251-infected rhesus macaques which contain frequent measurements throughout the entire course of the infection until the development of simian AIDS. Our model enables us to predict the survival times of the animals more accurately than an equivalent model which considers the viral set point only. Furthermore, we find that peaks of the virus load contribute less to disease progression than phases of low virus load with the same amount of viral turnover. Our analysis implies that the total viral turnover is not the best correlate of survival. As a consequence, the direct cytopathic effects of virus replication may, by themselves, have less of an impact on disease progression than previously thought.

Animals↗