265 research outputs found
For T Cell Receptors, Some Breakups Might Not Last Forever
Does the affinity or half-life of peptide-MHC-T cell receptor (TCR) interactions determine T cell activation? In this issue of Immunity, Aleksic et al. (2010) propose a role for the on rate through multiple rebindings to the same TCR
From HIV protein sequences to viral fitness landscapes: a new paradigm for in silico vaccine design
Background: An inexpensive prophylactic vaccine offers the best hope to curb the HIV/AIDS epidemic gripping sub-Saharan Africa. Systematic means to guide the design of an effective immunogen for this, and other, infectious diseases are not available. What is required is a method to chart the peaks and valleys of viral fitness as a function of amino acid sequence. An efficacious vaccine would eject the virus from the high fitness peaks, and drive it into the valleys where its compromised fitness impairs its ability to replicate and inflict damage to the host.
Methods: Appealing to spin glass models in statistical physics, we present a novel approach to translate viral sequence databases into landscapes of viral fitness. These inferred models furnish a quantitative description of viral replicative capacity as a function of amino acid sequence. We illustrate this approach in the development of landscapes for the proteins of HIV-1 clade B Gag.
Results: In comparisons to experimental and clinical data, our inferred landscapes demonstrate excellent agreement with: 1) in vitro replicative fitness measurements, 2) clinically observed high-fitness circulating viral strains, 3) documented HLA associated CTL escape mutations, and 4) intra-host temporal adaptation pathways revealed by deep sequencing. These favorable comparisons support our landscapes as reflections of intrinsic viral fitness. We illustrate the value of such descriptions in the computational design of a CTL Gag immunogen.
Conclusion: We present a novel methodology to translate viral sequence data into quantitative landscapes of viral fitness. In an application to HIV-1 Gag, we illustrate excellent agreement of our model predictions with experimental and clinical data, and demonstrate a powerful new approach for HIV immunogen design. We anticipate that this approach may represent a heretofore unprecedented means to synthesize fitness landscapes for diverse pathogens, and may provide the basis for the design of improved prophylactic and therapeutic strategies
Identification of drug resistance mutations in HIV from constraints on natural evolution
Human immunodeficiency virus (HIV) evolves with extraordinary rapidity.
However, its evolution is constrained by interactions between mutations in its
fitness landscape. Here we show that an Ising model describing these
interactions, inferred from sequence data obtained prior to the use of
antiretroviral drugs, can be used to identify clinically significant sites of
resistance mutations. Successful predictions of the resistance sites indicate
progress in the development of successful models of real viral evolution at the
single residue level, and suggest that our approach may be applied to help
design new therapies that are less prone to failure even where resistance data
is not yet available.Comment: 5 pages, 3 figure
A Population Dynamics Model for Clonal Diversity in a Germinal Center
Germinal centers (GCs) are micro-domains where B cells mature to develop high affinity antibodies. Inside a GC, B cells compete for antigen and T cell help, and the successful ones continue to evolve. New experimental results suggest that, under identical conditions, a wide spectrum of clonal diversity is observed in different GCs, and high affinity B cells are not always the ones selected. We use a birth, death and mutation model to study clonal competition in a GC over time. We find that, like all evolutionary processes, diversity loss is inherently stochastic. We study two selection mechanisms, birth-limited and death limited selection. While death limited selection maintains diversity and allows for slow clonal homogenization as affinity increases, birth limited selection results in more rapid takeover of successful clones. Finally, we qualitatively compare our model to experimental observations of clonal selection in mice
Deconvolving mutational patterns of poliovirus outbreaks reveals its intrinsic fitness landscape.
Vaccination has essentially eradicated poliovirus. Yet, its mutation rate is higher than that of viruses like HIV, for which no effective vaccine exists. To investigate this, we infer a fitness model for the poliovirus viral protein 1 (vp1), which successfully predicts in vitro fitness measurements. This is achieved by first developing a probabilistic model for the prevalence of vp1 sequences that enables us to isolate and remove data that are subject to strong vaccine-derived biases. The intrinsic fitness constraints derived for vp1, a capsid protein subject to antibody responses, are compared with those of analogous HIV proteins. We find that vp1 evolution is subject to tighter constraints, limiting its ability to evade vaccine-induced immune responses. Our analysis also indicates that circulating poliovirus strains in unimmunized populations serve as a reservoir that can seed outbreaks in spatio-temporally localized sub-optimally immunized populations
How nonuniform contact profiles of T cell receptors modulate thymic selection outcomes
T cell receptors (TCRs) bind foreign or self-peptides attached to major
histocompatibility complex (MHC) molecules, and the strength of this
interaction determines T cell activation. Optimizing the ability of T cells to
recognize a diversity of foreign peptides yet be tolerant of self-peptides is
crucial for the adaptive immune system to properly function. This is achieved
by selection of T cells in the thymus, where immature T cells expressing
unique, stochastically generated TCRs interact with a large number of
self-peptide-MHC; if a TCR does not bind strongly enough to any
self-peptide-MHC, or too strongly with at least one self-peptide-MHC, the T
cell dies. Past theoretical work cast thymic selection as an extreme value
problem, and characterized the statistical enrichment or depletion of amino
acids in the post-selection TCR repertoire, showing how T cells are selected to
be able to specifically recognize peptides derived from diverse pathogens, yet
have limited self-reactivity. Here, we investigate how the degree of enrichment
is modified by nonuniform contacts that a TCR makes with peptide-MHC.
Specifically, we were motivated by recent experiments showing that amino acids
at certain positions of a TCR sequence have large effects on thymic selection
outcomes, and crystal structure data that reveal a nonuniform contact profile
between a TCR and its peptide-MHC ligand. Using a representative TCR contact
profile as an illustration, we show via simulations that the degree of
enrichment now varies by position according to the contact profile, and,
importantly, it depends on the implementation of nonuniform contacts during
thymic selection. We explain these nontrivial results analytically. Our study
has implications for understanding the selection forces that shape the
functionality of the post-selection TCR repertoire.Comment: 10 pages, 4 figures, submitted to Phys. Rev.
Protein Clusters on the T Cell Surface May Suppress Spurious Early Signaling Events
T cells play an important role in the adaptive immune system, quickly activating effector functions in response to small numbers of antigenic peptides but rarely activating in response to constant interaction with most endogenous peptides. Emerging experimental evidence suggests that key membrane-bound signaling proteins such as the T cell receptor and the adaptor protein Lat are spatially organized into small clusters on the T cell membrane. We use spatially resolved, stochastic computer simulations to study how the inhomogeneous distribution of molecules affects the portion of the T cell signaling network in which the kinase ZAP-70, originating in T cell receptor clusters, phosphorylates Lat. To gain insight into the effects of protein clustering, we compare the signaling response from membranes with clustered proteins to the signaling response from membranes with homogeneously distributed proteins. Given a fixed amount of ZAP-70 (a proxy for degree of TCR stimulation) that must diffuse into contact with Lat molecules, the spatially homogeneous system responds faster and results in higher levels of phosphorylated Lat. Analysis of the spatial distribution of proteins demonstrates that, in the homogeneous system, nearest ZAP-70 and Lat proteins are closer on average and fewer Lat molecules share the same closest ZAP-70 molecule, leading to the faster response time. The results presented here suggest that spatial clustering of proteins on the T cell membrane may suppress the propagation of signal from ZAP-70 to Lat, thus providing a regulatory mechanism by which T cells suppress transient, spurious signals induced by stimulation of T cell receptors by endogenous peptides. Because this suppression of spurious signals may occur at a cost to sensitivity, we discuss recent experimental results suggesting other potential mechanisms by which ZAP-70 and Lat may interact to initiate T cell activation.United States. National Institutes of Health (Grant 1P01AI091580-01
Positive Feedback Regulation Results in Spatial Clustering and Fast Spreading of Active Signaling Molecules on a Cell Membrane
Positive feedback regulation is ubiquitous in cell signaling networks, often
leading to binary outcomes in response to graded stimuli. However, the role of
such feedbacks in clustering, and in spatial spreading of activated molecules,
has come to be appreciated only recently. We focus on the latter, using a
simple model developed in the context of Ras activation with competing negative
and positive feedback mechanisms. We find that positive feedback, in the
presence of slow diffusion, results in clustering of activated molecules on the
plasma membrane, and rapid spatial spreading as the front of the cluster
propagates with a constant velocity (dependent on the feedback strength). The
advancing fronts of the clusters of the activated species are rough, with
scaling consistent with the Kardar-Parisi-Zhang (KPZ) equation in one
dimension. Our minimal model is general enough to describe signal transduction
in a wide variety of biological networks where activity in the
membrane-proximal region is subject to feedback regulation.Comment: 37 pages, 8 figures. Journal of Chemical Physics (in press
Scaling laws describe memories of host–pathogen riposte in the HIV population
The enormous genetic diversity and mutability of HIV has prevented effective control of this virus by natural immune responses or vaccination. Evolution of the circulating HIV population has thus occurred in response to diverse, ultimately ineffective, immune selection pressures that randomly change from host to host. We show that the interplay between the diversity of human immune responses and the ways that HIV mutates to evade them results in distinct sets of sequences defined by similar collectively coupled mutations. Scaling laws that relate these sets of sequences resemble those observed in linguistics and other branches of inquiry, and dynamics reminiscent of neural networks are observed. Like neural networks that store memories of past stimulation, the circulating HIV population stores memories of host–pathogen combat won by the virus. We describe an exactly solvable model that captures the main qualitative features of the sets of sequences and a simple mechanistic model for the origin of the observed scaling laws. Our results define collective mutational pathways used by HIV to evade human immune responses, which could guide vaccine design.Ragon Institute of MGH, MIT and Harvar
- …