These data show that despite relatively high sequence variability, viral regions within the clade B consensus sequence of Nef are preferentially recognized during primary HIV-1 infection. Later diversification of responses to other proteins during prolonged antigen exposure provides evidence of the initial preferential immunogenicity of Nef epitopes compared to similarly conserved regions within other viral proteins.
The phenotypic effect of prions on host cells is influenced by the physical properties of the prion strain and its level of accumulation. In mammalian cell cultures, prion accumulation is determined by the interplay between de novo prion formation, catabolism, cell division, and horizontal cell-to-cell transmission. Understanding this dynamic enables the analytical modeling of protein-based heritability and infectivity. Here, we quantitatively measured these competing effects in a subline of neuroblastoma (N2a) cells and propose a concordant reaction mechanism to explain the kinetics of prion propagation. Our results show that cell division leads to a predictable reduction in steady-state prion levels but not to complete clearance. Scrapie-infected N2a cells were capable of accumulating different steady-state levels of prions, dictated partly by the rate of cell division. We also show that prions in this subline of N2a cells are transmitted primarily from mother to daughter cells, rather than horizontal cell-to-cell transmission. We quantitatively modeled our kinetic results based on a mechanism that assumes a subpopulation of prions is capable of self-catalysis, and the levels of this subpopulation reach saturation in fully infected cells. Our results suggest that the apparent effectiveness of antiprion compounds in culture may be strongly influenced by the growth phase of the target cells.kinetics ͉ neuroblastoma ͉ prion propagation ͉ limited conversion model ͉ steady state
Human immunodeficiency virus type 1 (HIV-1) mutates to escape immune selection pressure, but there is little evidence of selection mediated through HLA-A2, the dominant class I allele in persons infected with clade B virus. Moreover, HLA-A2-restricted responses are largely absent in the acute phase of infection as the viral load is being reduced, suggesting that circulating viruses may lack immunodominant epitopes targeted through HLA-A2. Here we demonstrate an A2-restricted epitope within Vpr (Vpr 59-67 ) that is targeted by acute-phase HIV-1-specific CD8 ؉ T cells, but only in a subset of persons expressing HLA-A2. Individuals in the acute stage of infection with viruses containing the most common current sequence within this epitope (consensus sequence) were unable to mount epitope-specific T-cell responses, whereas subjects infected with the less frequent I 60 L variant all developed these responses. The I 60 L variant epitope was a stronger binder to HLA-A2 and was recognized by epitope-specific T cells at lower peptide concentrations than the consensus sequence epitope. These data demonstrate that HLA-A2 is capable of contributing to the acute-phase cytotoxic Tlymphocyte response in infected subjects, but that most currently circulating viruses lack a dominant immunogenic epitope presented by this allele, and suggest that immunodominant epitopes restricted by common HLA alleles may be lost as the epidemic matures.The human immunodeficiency virus type 1 (HIV-1) epidemic is characterized by a high genetic diversity within the viral population that results from high replication and mutation rates in the presence of immunological selection pressure (29). Viral strains from the same HIV-1 clade can differ by 25% at the amino acid level, depending on the particular HIV-1 protein under consideration (29). This substantial sequence diversity poses a major challenge to the design of vaccines capable of inducing cross-reactive CD8 ϩ T-cell responses. As a consequence, the use of clade-specific consensus sequences has been recently proposed for vaccine design (12). Clade consensus sequences have the advantage of being most similar to currently circulating strains of interest, with each amino acid corresponding to the most commonly found amino acid at that position within the overall viral population.A number of studies have demonstrated that HIV-1 can rapidly escape from CD8 ϩ T-cell-mediated immune pressure by sequence variation within or flanking targeted epitopes (1,6,11,14,15,18,20,(23)(24)(25). The accumulation of escape variants within epitopes presented by the HLA class I alleles expressed in an infected individual can result in "HLA footprints" on the viral sequence (21,22,30). Recent data demonstrate that these cytotoxic T-lymphocyte (CTL) escape variants can be transmitted and impair the generation of otherwise immunodominant immune responses during primary infection in a new host (1,14,20). The rate at which these sequence mutations within epitopes may accumulate in the viral population largely depends on ...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.