11,466 research outputs found

    Deleterious synonymous mutations hitchhike to high frequency in HIV-1 env evolution

    Full text link
    Intrapatient HIV-1 evolution is dominated by selection on the protein level in the arms race with the adaptive immune system. When cytotoxic CD8+ T-cells or neutralizing antibodies target a new epitope, the virus often escapes via nonsynonymous mutations that impair recognition. Synonymous mutations do not affect this interplay and are often assumed to be neutral. We analyze longitudinal intrapatient data from the C2-V5 part of the envelope gene (env) and observe that synonymous derived alleles rarely fix even though they often reach high frequencies in the viral population. We find that synonymous mutations that disrupt base pairs in RNA stems flanking the variable loops of gp120 are more likely to be lost than other synonymous changes, hinting at a direct fitness effect of these stem-loop structures in the HIV-1 RNA. Computational modeling indicates that these synonymous mutations have a (Malthusian) selection coefficient of the order of -0.002 and that they are brought up to high frequency by hitchhiking on neighboring beneficial nonsynonymous alleles. The patterns of fixation of nonsynonymous mutations estimated from the longitudinal data and comparisons with computer models suggest that escape mutations in C2-V5 are only transiently beneficial, either because the immune system is catching up or because of competition between equivalent escapes

    Scaling in the immune system

    Get PDF
    How different is the immune system in a human from that of a mouse? Do pathogens replicate at the same rate in different species? Answers to these questions have impact on human health since multi-host pathogens that jump from animals to humans affect millions worldwide. It is not known how rates of immune response and viral dynamics vary from species to species and how they depend on species body size. Metabolic scaling theory predicts that intracellular processes are slower in larger animals since cellular metabolic rates are slower. We test how rates of pathogenesis and immune system response rates depend on species body size. We hypothesize that immune response rates are invariant with body size. Our work suggests how the physical architecture of the immune system and chemical signals within it may lead to nearly scale-invariant immune search and response. We fit mathematical models to experimental West Nile Virus (WNV, a multi-host pathogen) infection data and investigate how model parameters characterizing the pathogen and the immune response change with respect to animal mass. Phylogeny also affects pathogenesis and immune response. We use a hierarchical Bayesian model, that incorporates phylogeny, to test hypotheses about the role of mass and phylogeny on pathogen replication and immune response. We observe that: 1) Hierarchical models (informed by phylogeny) make more accurate predictions of experimental data and more realistic estimates of biologically relevant parameters characterizing WNV infection. 2) Rates of WNV production decline with species body mass, modified by a phylogenetic influence. Our work is the first to systematically explore the role of host body mass in pathogenesis using mathematical models and empirical data. We investigate the complex interplay between the physical structure of the immune system and host body mass in determining immune response. The modeling strategies and tools outlined here are likely to be applicable to modeling of other multi-host pathogens. This work could also be extended to understand how drug and vaccine efficacy differ in humans from model organisms like mice where most immunological experiments are conducted
    • …
    corecore