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Biomedical subjects

Sebastian Bonhoeffer

Publications and source records attributed to Sebastian Bonhoeffer.

At least 37 records · Page 2Linked to original sources
PubMed2005

The HIV coreceptor switch: a population dynamical perspective.

Over the course of infection, the coreceptor usage of the HIV virus changes from a preference for CCR5 to a preference for CXCR4 in approximately 50% of infected individuals. The change in coreceptor usage is the result of the complex interaction of the viral population with various cell populations of the immune system. Although many of the molecular processes involved in viral attachment and entry have been resolved, the population dynamical mechanisms leading to the emergence of CXCR4-using HIV variants in some infected individuals are not yet understood. Here, we review various hypotheses that have been proposed to explain the change of HIV coreceptor usage in the course of infection, and conclude that any corroboration or rejection of these hypotheses requires a quantitative analysis of the interaction between the virus and immune cells.

Disease Progression↗
PubMed2005

Short communication: HIV type 2 dynamics.

To gain a better understanding of why HIV-2 is less virulent than HIV-1 the viral dynamics of HIV-2 were studied in two Swedish HIV-2-infected patients after starting antiretroviral therapy. Linear regression analysis of log virus levels in plasma showed that virus decline during the first 2 weeks of therapy followed an exponential decay with half-lives of 2.2 and 2.0 days, respectively. These half-life measurements reflect the decline in the number of cells actively producing the virus, but may represent an underestimation of the true turnover of HIV-2. In one patient, preliminary estimates of the first and second phase of virus decline (halflife 1.3 and 15 days, respectively) were made. The viral dynamics of HIV-2 infection are strikingly similar to those for HIV-1. Thus, HIV-1 and HIV-2 appear to have similar rates of production and clearance in vivo. Consequently, the large differences in plasma virus levels, virulence, and natural course of the disease between the two infections are due to other factors that are yet to be identified.

Adult↗
PubMed2005

Stochastic interplay between mutation and recombination during the acquisition of drug resistance mutations in human immunodeficiency virus type 1.

The emergence of drug resistance mutations in human immunodeficiency virus (HIV) has been a major setback in the treatment of infected patients. Besides the high mutation rate, recombination has been conjectured to have an important impact on the emergence of drug resistance. Population genetic theory suggests that in populations limited in size recombination may facilitate the acquisition of beneficial mutations. The viral population in an infected patient may indeed represent such a population limited in size, since current estimates of the effective population size range from 500 to 10(5). To address the effects of limited population size, we therefore expand a previously described deterministic population genetic model of HIV replication by incorporating the stochastic processes that occur in finite populations of infected cells. Using parameter estimates from the literature, we simulate the evolution of drug-resistant viral strains. The simulations show that recombination has only a minor effect on the rate of acquisition of drug resistance mutations in populations with effective population sizes as small as 1,000, since in these populations, viral strains typically fix beneficial mutations sequentially. However, for intermediate effective population sizes (10(4) to 10(5)), recombination can accelerate the evolution of drug resistance by up to 25%. Furthermore, a reduction in population size caused by drug therapy can be overcome by a higher viral mutation rate, leading to a faster evolution of drug resistance.

Anti-HIV Agents↗
PubMed2004

Epitope down-modulation as a mechanism for the coexistence of competing T-cells.

Efficient immune responses against pathogens are frequently characterized by the simultaneous targeting of multiple epitopes. However, it remains unclear how the targeting of multiple epitopes is maintained in the face of competition for antigenic stimulation. Here, we investigate this question by using mathematical models of the population dynamics of a viral pathogen, antigen presentation sites and T-cells. We first show that direct competition for access to antigen presenting sites and indirect competition through killing of the pathogen select for dominance of the T-cell response with the highest affinity for its epitope. We then incorporate in our model that epitopes can become down-modulated following interaction with epitope specific T-cells. We demonstrate that epitope down-modulation leads to differentiation of epitope presentation on antigen presenting sites. This differentiation promotes the coexistence of multiple epitope specific responses. Hence, we propose that the functional relevance of epitope down-modulation may be to enable the persistence of a broad immune response despite competition for antigenic stimulation.

Animals↗
PubMed2004

Evidence for positive epistasis in HIV-1.

Reproductive strategies such as sexual reproduction and recombination that involve the shuffling of parental genomes for the production of offspring are ubiquitous in nature. However, their evolutionary benefit remains unclear. Many theories have identified potential benefits, but progress is hampered by the scarcity of relevant data. One class of theories is based on the assumption that mutations affecting fitness exhibit negative epistasis. Retroviruses recombine frequently and thus provide a unique opportunity to test these theories. Using amino acid sequence data and fitness values from 9466 human immunodeficiency virus 1 (HIV-1) isolates, we find in contrast to these theories strong statistical evidence for a predominance of positive epistasis in HIV-1.

Amino Acid Sequence↗
PubMed2004

Spatial models of virus-immune dynamics.

To date, the majority of theoretical models describing the dynamics of infectious diseases in vivo are based on the assumption of well-mixed virus and cell populations. Because many infections take place in solid tissues, spatially structured models represent an important step forward in understanding what happens when the assumption of well-mixed populations is relaxed. Here, we explore models of virus and virus-immune dynamics where dispersal of virus and immune effector cells was constrained to occur locally. The stability properties of our spatial virus-immune dynamics models remained robust under almost all biologically plausible dispersal schemes, regardless of their complexity. The various spatial dynamics were compared to the basic non-spatial dynamics and important differences were identified: When space was assumed to be homogeneous, the dynamics generated by non-spatial and spatially structured models differed substantially at the peak of the infection. Thus, non-spatial models may lead to systematic errors in the estimates of parameters underlying acute infection dynamics. When space was assumed to be heterogeneous, spatial coupling not only changed the equilibrium properties of the uncoupled populations but also equalized the dynamics and thereby reduced the likelihood of dynamic elimination of the infection. In line with experimental and clinical observations, long-lasting oscillation periods were virtually absent. When source-sink dynamics were considered, the long-term outcome of the infection depended critically on the degree of spatial coupling. The infection collapsed when emigration from source sites became too large. Finally, we discuss the implications of spatially structured models on medical treatment of infectious diseases, and note that a huge gap exists in data accurately describing infection dynamics in solid tissues.

Chronic Disease↗
PubMed2004

Quantification of infectious HIV-1 plasma viral load using a boosted in vitro infection protocol.

Methods currently used for HIV-1 viral load measurements are very sensitive, but cannot distinguish between infectious and noninfectious particles. Here we describe the development of a novel, sensitive, and highly reproducible method that allows rapid isolation and quantification of infectious particles from patient plasma. By immobilizing HIV-1 particles in human plasma to platelets using polybrene, we observed a 10- to 1000-fold increase in infectivity over infection protocols using free virus particles. Using this method, we evaluated infectivity in plasma from 52 patients at various disease stages. At plasma viral loads of 1000-10000 HIV-1 RNA copies/ml 18%, at 10,000-50,000 copies/ml 73%, at 50,000-100,000 copies/ml 90%, and above 100,000 copies 96% of cultures were positive. We found that infectious titers among patients vary distinctively but are characteristic for a patient over extended time periods. Furthermore, we demonstrate that by evaluating infectious titers in conjunction with total HIV RNA loads, subtle effects of treatment intervention on viremia levels can be detected. The immobilization procedure does not interfere with viral entry and does not restore the infectivity of neutralized virus. Therefore, this assay system can be utilized to investigate the influence of substances that specifically affect virion infectivity such as neutralizing antibodies, soluble CD4, or protease inhibitors. Measuring viral infectivity may thereby function as an additional, useful marker in monitoring disease progression and evaluating efficacy of antivirals in vivo.

Adult↗
PubMed2004

Humoral immunity to HIV-1: kinetics of antibody responses in chronic infection reflects capacity of immune system to improve viral set point.

We analyzed the humoral immune response in 46 patients following structured treatment interruption (STI) to investigate the general potential of therapeutic vaccination in chronic HIV-1 infection. Evoked antibody titer increases to glycoprotein 120 (gp120) and p24 were low during 4 short-term STIs and only reached significance during a fifth long-term interruption. Although induction of binding antibodies to viral antigens was not associated with potent suppression of viremia, we observed that individuals with a rapid and high response to p24, and to a lesser extent also to gp120, lowered their viral set points significantly. Of note, the increase of the anti-p24 response correlated with specific CD4 T helper frequency to this antigen. Despite induction of binding antibody responses, which correlated with improved viral control, the increase in neutralizing activity was marginal and did not lead to this enhanced viral suppression. However, a subgroup of patients who potently suppressed viremia independently of STI had significantly higher pre-existing neutralization titers, suggesting a role of humoral immunity in conferring potent protection. In summary, measuring the kinetics of antibody responses provided a marker to validate the responsiveness and capacities of the immune system of HIV-1-infected individuals and reflected the patients' ability to decrease viral set points.

Adult↗
PubMed2004

Evolution of cross-feeding in microbial populations.

Although limited by a single resource, microbial populations that grow for long periods in continuous culture (chemostat) frequently evolve stable polymorphisms. These polymorphisms may be maintained by cross-feeding, where one strain partially degrades the primary energy resource and excretes an intermediate that is used as an energy resource by a second strain. It is unclear what selective advantage cross-feeding strains have over a single competitor that completely degrades the primary resource. Here we show that cross-feeding may evolve in microbial populations as a consequence of the following optimization principles: the rate of ATP production is maximized, the concentration of enzymes of the pathway is minimized, and the concentration of intermediates of the pathway is minimized.

Adaptation, Physiological↗
PubMed2004

Interchromatid and interhomolog recombination in Arabidopsis thaliana.

Intermolecular recombination events were monitored in Arabidopsis thaliana lines using specially designed recombination traps consisting of tandem disrupted beta-glucuronidase or luciferase reporter genes in direct repeat orientation. Recombination frequencies (RFs) varied between the different lines, indicating possible position effects influencing intermolecular recombination processes. The RFs between sister chromatids and between homologous chromosomes were measured in plants either hemizygous or homozygous for a transgene locus. The RFs in homozygous plants exceeded those of hemizygous plants by a factor of >2, implying that in somatic plant cells both sister chromatid recombination and recombination between homologous chromosomes exist for recombinational DNA repair. In addition, different DNA-damaging agents stimulated recombination in homozygous and hemizygous plants to different extents in a manner dependent on the type of DNA damage and on the genomic region. The genetic and molecular analysis of recombination events showed that most of the somatic recombination events result from gene conversion, although a pop-out event has also been characterized.

Arabidopsis↗
PubMed2004

Recombination in HIV and the evolution of drug resistance: for better or for worse?

The rapid evolution of drug resistance remains a major obstacle for HIV therapy. The capacity of the virus for recombination is widely believed to facilitate the evolution of drug resistance. Here, we challenge this intuitive view. We develop a population genetic model of HIV replication that incorporates the processes of mutation, cellular superinfection, and recombination. We show that cellular superinfection increases the abundance of low fitness viruses at the expense of the fittest strains due to the mixing of viral proteins during virion assembly. Moreover, we argue that whether recombination facilitates the evolution of drug resistance depends critically on how resistance mutations interact to determine viral fitness. Contrary to the commonly held belief, we find that, under the most plausible biological assumptions, recombination is expected to slow down the rate of evolution of multi-drug-resistant virus during therapy.

Drug Resistance, Viral↗
PubMed2004

Entry and transcription as key determinants of differences in CD4 T-cell permissiveness to human immunodeficiency virus type 1 infection.

Isolated primary human cells from different donors vary in their permissiveness-the ability of cells to be infected and sustain the replication of human immunodeficiency virus type 1 (HIV-1). We used replicating HIV-1 and single-cycle lentivirus vectors in a population approach to identify polymorphic steps during viral replication. We found that phytohemagglutinin-stimulated CD4(+) CD45RO(+) CD57(-) T cells from healthy blood donors (n = 128) exhibited a 5.2-log-unit range in virus production. For 20 selected donors representing the spectrum of CD4 T-cell permissiveness, we could attribute up to 42% of the total variance in virus production to entry factors and 48% to postentry steps. Efficacy at key intracellular steps of the replicative cycle (reverse transcription, integration, transcription and splicing, translation, and budding and release) varied from 0.71 to 1.45 log units among donors. However, interindividual differences in transcription efficiency alone accounted for 64 to 83% of the total variance in virus production that was attributable to postentry factors. While vesicular stomatitis virus G protein-mediated fusion was more efficacious than CCR5/CD4 entry, the latter resulted in greater transcriptional activity per proviral copy. The phenotype of provirus transcription was stable over time, indicating that it represents a genetic trait.

Biological Transport↗
PubMed2003

Emergence of minor populations of human immunodeficiency virus type 1 carrying the M184V and L90M mutations in subjects undergoing structured treatment interruptions.

The use of structured treatment interruption (STI) in human immunodeficiency virus (HIV)-infected subjects is currently being studied as an alternative therapeutic strategy for HIV-1. The potential risk for selection of drug-resistant HIV-1 variants during STI is unknown and remains a concern. Therefore, the emergence of drug resistance in sequential plasma samples obtained from 28 subjects with chronic HIV infection was studied. They underwent 4 cycles of 2-week STI, followed by 8-week retreatment with highly active antiretroviral therapy identical to that used before STI, and they had never failed treatment before undergoing STI. At week 40, treatment was stopped for a longer period. Minor populations of drug-resistant variants were detected by quantitative real-time polymerase chain reaction, by use of allele-discriminating oligonucleotides for 2 key resistance mutations: L90M (protease) and M184V (reverse transcriptase). The approximate discriminative power was 0.1%. In 14 of 25 and in 3 of 25 subjects, the M184V and the L90M mutations, respectively, were detected as minor populations, at different times during STI. Overall, these results indicate that, in subjects undergoing multiple STIs, HIV-1 variants carrying drug-resistance mutations can emerge during periods of increased HIV-1 replication.

Adult↗
PubMed2003

An evolutionary scenario for the transition to undifferentiated multicellularity.

The evolutionary transition from single cells toward multicellular forms of life represents one of the major transitions in the evolution of complex organisms. In this transition, single autonomously reproducing cells became parts of larger reproducing entities that eventually constituted a new unit of selection. The first step in the evolutionary transition to multicellularity likely was the evolution of simple, undifferentiated cell clusters. However, what the selective advantage of such cell clusters may have been remains unclear. Here, we argue that in populations of unicellular organisms with cooperative behavior, clustering may be beneficial by reducing interactions with noncooperative individuals. In support of this hypothesis, we present a set of computer simulations showing that clustering can evolve as a biological, heritable trait for cells that cooperate in the use of external energy resources. Following the evolution of simple cell clusters, further benefits could have arisen from the exchange of resources between cells of a cluster.

Adenosine Triphosphate↗
PubMed2003

Glancing behind virus load variation in HIV-1 infection.

Although the steady-state virus load during HIV-1 infection is remarkably stable within a patient, it displays variation over several orders of magnitude between patients. Despite intensive research, the host and virus factors that are responsible for the observed variation remain poorly understood. Comparison of model predictions with clinical data suggests that most of the variation in steady-state virus load between patients reflects variation of the net rate at which activated CD4 cells are produced.

Genetic Variation↗
PubMed2003

Quantitative constraints on the scope of negative selection.

Maturing T cells with a high affinity for self-antigens presented in the thymus are deleted in the process of negative selection. Although the expression of various "tissue-specific" antigens has been described in the thymus, it is still controversial what fraction of all self-antigens induces tolerance by this mechanism. We demonstrate that the limited duration of the negative selection phase imposes a constraint on the number of self-peptides that can be reliably selected against. The analysis supports the theory that negative selection is confined to the subset of peptides produced by dendritic cells.

Animals↗