Evidence of CD4+ T cell-mediated immune pressure on the Hepatitis C virus genome

Hepatitis C virus (HCV)-specific T cell responses are critical for immune control of infection. Viral adaptation to these responses, via mutations within regions of the virus targeted by CD8+ T cells, is associated with viral persistence. However, identifying viral adaptation to HCV-specific CD4+ T cell responses has been difficult although key to understanding anti-HCV immunity. In this context, HCV sequence and host genotype from a single source HCV genotype 1B cohort (n = 63) were analyzed to identify viral changes associated with specific human leucocyte antigen (HLA) class II alleles, as these variable host molecules determine the set of viral peptides presented to CD4+ T cells. Eight sites across the HCV genome were associated with HLA class II alleles implicated in infection outcome in this cohort (p ≤ 0.01; Fisher’s exact test). We extended this analysis to chronic HCV infection (n = 351) for the common genotypes 1A and 3A. Variation at 38 sites across the HCV genome were associated with specific HLA class II alleles with no overlap between genotypes, suggestive of genotype-specific T cell targets, which has important implications for vaccine design. Here we show evidence of HCV adaptation to HLA class II-restricted CD4+ T cell pressure across the HCV genome in chronic HCV infection without a priori knowledge of CD4+ T cell epitopes

Progenitor and terminal subsets of CD8+ T cells cooperate to contain chronic viral infection.

Chronic infections strain the regenerative capacity of antiviral T lymphocyte populations, leading to failure in long-term immunity. The cellular and molecular events controlling this regenerative capacity, however, are unknown. We found that two distinct states of virus-specific CD8(+) T cells exist in chronically infected mice and humans. Differential expression of the T-box transcription factors T-bet and Eomesodermin (Eomes) facilitated the cooperative maintenance of the pool of antiviral CD8(+) T cells during chronic viral infection. T-bet(hi) cells displayed low intrinsic turnover but proliferated in response to persisting antigen, giving rise to Eomes(hi) terminal progeny. Genetic elimination of either subset resulted in failure to control chronic infection, which suggests that an imbalance in differentiation and renewal could underlie the collapse of immunity in humans with chronic infections

Gelation of particles with short-range attraction

Nanoscale or colloidal particles are important in many realms of science and technology. They can dramatically change the properties of materials, imparting solid-like behaviour to a wide variety of complex fluids1, 2. This behaviour arises when particles aggregate to form mesoscopic clusters and networks. The essential component leading to aggregation is an interparticle attraction, which can be generated by many physical and chemical mechanisms. In the limit of irreversible aggregation, infinitely strong interparticle bonds lead to diffusion-limited cluster aggregation3 (DLCA). This is understood as a purely kinetic phenomenon that can form solid-like gels at arbitrarily low particle volume fraction4, 5. Far more important technologically are systems with weaker attractions, where gel formation requires higher volume fractions. Numerous scenarios for gelation have been proposed, including DLCA6, kinetic or dynamic arrest4, 7, 8, 9, 10, phase separation5, 6, 11, 12, 13, 14, 15, 16, percolation4, 12, 17, 18 and jamming8. No consensus has emerged and, despite its ubiquity and significance, gelation is far from understood—even the location of the gelation phase boundary is not agreed on5. Here we report experiments showing that gelation of spherical particles with isotropic, short-range attractions is initiated by spinodal decomposition; this thermodynamic instability triggers the formation of density fluctuations, leading to spanning clusters that dynamically arrest to create a gel. This simple picture of gelation does not depend on microscopic system-specific details, and should thus apply broadly to any particle system with short-range attractions. Our results suggest that gelation—often considered a purely kinetic phenomenon4, 8, 9, 10—is in fact a direct consequence of equilibrium liquid–gas phase separation5, 13, 14, 15. Without exception, we observe gelation in all of our samples predicted by theory and simulation to phase-separate; this suggests that it is phase separation, not percolation12, that corresponds to gelation in models for attractive spheres