From HIV infection to AIDS: A dynamically induced percolation transition?

The origin of the unusual incubation period distribution in the development of AIDS is largely unresolved. A key factor in understanding the observed distribution of latency periods, as well as the occurrence of infected individuals not developing AIDS at all, is the dynamics of the long lasting struggle between HIV and the immune system. Using a computer simulation, we study the diversification of viral genomes under mutation and the selective pressure of the immune system.In common infections vast spreading of viral genomes usually does not takes place. In the case of an HIV infection this may occur, as the virus successively weakens the immune system by depletion of CD4+ cells.In a sequence space framework, this leads to a dynamically induced percolation transition, corresponding to the onset of AIDS. As a result, we obtain the prolongated shape of the incubation period distribution, as well as a finite fraction of non-progressors that do not develop AIDS, comparing well with results from recent clinical research.Comment: 7 pages RevTeX, 4 figure

Understanding the HIV coreceptor switch from a dynamical perspective

<p>Abstract</p> <p>Background</p> <p>The entry of HIV into its target cells is facilitated by the prior binding to the cell surface molecule CD4 and a secondary coreceptor, mostly the chemokine receptors CCR5 or CXCR4. In early infection CCR5-using viruses (R5 viruses) are mostly dominant while a receptor switch towards CXCR4 occurs in about 50% of the infected individuals (X4 viruses) which is associated with a progression of the disease. There are many hypotheses regarding the underlying dynamics without yet a conclusive understanding.</p> <p>Results</p> <p>While it is difficult to isolate key factors <it>in vivo </it>we have developed a minimal <it>in silico </it>model based on the approaches of Nowak and May to investigate the conditions under which the receptor switch occurs. The model allows to investigate the evolution of viral strains within a probabilistic framework along the three stages of disease from primary and latent infection to the onset of AIDS with a a sudden increase in viral load which goes along with the impairment of the immune response. The model is specifically applied to investigate the evolution of the viral quasispecies in terms of R5 and X4 viruses which directly translates into the composition of viral load and consequently the question of the coreceptor switch.</p> <p>Conclusion</p> <p>The model can explain the coreceptor switch as a result of a dynamical change in the underlying environmental conditions in the host. The emergence of X4 strains does not necessarily result in the dominance of X4 viruses in viral load which is more likely to occur in the model after some time of chronic infection. A better understanding of the conditions leading to the coreceptor switch is especially of interest as CCR5 blockers have recently been licensed as drugs which suppress R5 viruses but do not seem to necessarily induce a coreceptor switch.</p

Viral evolution under the pressure of an adaptive immune system - optimal mutation rates for viral escape

Based on a recent model of evolving viruses competing with an adapting immune system [1], we study the conditions under which a viral quasispecies can maximize its growth rate. The range of mutation rates that allows viruses to thrive is limited from above due to genomic information deterioration, and from below by insufficient sequence diversity, which leads to a quick eradication of the virus by the immune system. The mutation rate that optimally balances these two requirements depends to first order on the ratio of the inverse of the virus' growth rate and the time the immune system needs to develop a specific answer to an antigen. We find that a virus is most viable if it generates exactly one mutation within the time it takes for the immune system to adapt to a new viral epitope. Experimental viral mutation rates, in particular for HIV (human immunodeficiency virus), seem to suggest that many viruses have achieved their optimal mutation rate. [1] C.Kamp and S. Bornholdt, Phys. Rev. Lett., 88, 068104 (2002)Comment: 5 pages RevTeX including 3 figure

Dynamical suppression of large instantons

We investigate the distribution of instanton sizes in the framework of a simplified model for ensembles of instantons. This model takes into account the non-diluteness of instantons. The infrared problem for the integration over instanton sizes is dealt with in a self-consistent manner by approximating instanton interactions by a repulsive hard core potential. This leads to a dynamical suppression of large instantons. The characteristic features of the instanton size distribution are studied by means of analytic and Monte Carlo methods. We find a power law behaviour for small sizes, consistent with the semi-classical results. At large instanton sizes the distribution decays exponentially. The results are compared with those from lattice simulations.Comment: 2 pages, 1 figure, talk presented at Lattice2001(confinement

Spectral Analysis of Protein-Protein Interactions in Drosophila melanogaster

Within a case study on the protein-protein interaction network (PIN) of Drosophila melanogaster we investigate the relation between the network's spectral properties and its structural features such as the prevalence of specific subgraphs or duplicate nodes as a result of its evolutionary history. The discrete part of the spectral density shows fingerprints of the PIN's topological features including a preference for loop structures. Duplicate nodes are another prominent feature of PINs and we discuss their representation in the PIN's spectrum as well as their biological implications.Comment: 9 pages RevTeX including 8 figure

Driving change in dtap batch release testing

The complexity of vaccine manufacturing has raised the need to drive standardization and quality control requirements as well as batch release of vaccines. The purpose of release testing is to ensure that efficacy and safety of the vaccine product are maintained in all batches. Classical testing includes challenge experiments in animals that provide proof of vaccine potency and identify subpotent vaccines. However, novel concepts such as “consistency testing” question the continued need for in vivo experiments and propose to implement rigorous QC for lot-to-lot consistency testing with other methods at an earlier stage. Please click Download on the upper right corner to see the full abstract

Cancer, Warts, or Asymptomatic Infections: Clinical Presentation Matches Codon Usage Preferences in Human Papillomaviruses

Viruses rely completely on the hosts' machinery for translation of viral transcripts. However, for most viruses infecting humans, codon usage preferences (CUPrefs) do not match those of the host. Human papillomaviruses (HPVs) are a showcase to tackle this paradox: they present a large genotypic diversity and a broad range of phenotypic presentations, from asymptomatic infections to productive lesions and cancer. By applying phylogenetic inference and dimensionality reduction methods, we demonstrate first that genes in HPVs are poorly adapted to the average human CUPrefs, the only exception being capsid genes in viruses causing productive lesions. Phylogenetic relationships between HPVs explained only a small proportion of CUPrefs variation. Instead, the most important explanatory factor for viral CUPrefs was infection phenotype, as orthologous genes in viruses with similar clinical presentation displayed similar CUPrefs. Moreover, viral genes with similar spatiotemporal expression patterns also showed similar CUPrefs. Our results suggest that CUPrefs in HPVs reflect either variations in the mutation bias or differential selection pressures depending on the clinical presentation and expression timing. We propose that poor viral CUPrefs may be central to a trade-off between strong viral gene expression and the potential for eliciting protective immune response

Evolution of protein complexes by duplication of homomeric interactions.

BACKGROUND: Cellular functions are accomplished by the concerted actions of functional modules. The mechanisms driving the emergence and evolution of these modules are still unclear. Here we investigate the evolutionary origins of protein complexes, modules in physical protein-protein interaction networks. RESULTS: We studied protein complexes in Saccharomyces cerevisiae, complexes of known three-dimensional structure in the Protein Data Bank and clusters of pairwise protein interactions in the networks of several organisms. We found that duplication of homomeric interactions, a large class of protein interactions, frequently results in the formation of complexes of paralogous proteins. This route is a common mechanism for the evolution of complexes and clusters of protein interactions. Our conclusions are further confirmed by theoretical modelling of network evolution. We propose reasons for why this is favourable in terms of structure and function of protein complexes. CONCLUSION: Our study provides the first insight into the evolution of functional modularity in protein-protein interaction networks, and the origins of a large class of protein complexes