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Lentiviruses are single-stranded RNA viruses generally associated with chronic diseases of the immune and central nervous systems. In contrast to the insidious, progressive nature of most lentiviral diseases, equine infectious anemia virus (EIAV) infection results in rapid onset of a variable disease course in equids. Acute disease is accompanied with high-titered viremia, thrombocytopenia, fever, depression, and inappetance. The chronic stage is usually characterized by recurrent episodes of disease. Equids that survive recurrent disease episodes progress to the inapparent stage of disease were no clinical signs are evident; however, there is persistent, ongoing virus replication. Lentiviruses exist within the host as a population of closely related genotypes, termed as quasispecies. Variation in the virus surface unit envelope glycoprotein (SU) has been demonstrated to contribute to immune evasion of host responses during chronic disease. However, little is known about the SU genotypes and phenotypes associated with disease progression to the inapparent stage of disease. The goal of this research is a genotypic and phenotypic characterization of the SU quasispecies during clinical and inapparent stages of disease. To accomplish this goal, I undertook a longitudinal study of SU variation in a pony experimentally inoculated with the virulent, wild-type, EIAV[subscript Wyo]. There was a marked increase in quasispecies diversity and divergence that coincided with maturation of the immune response and progression to the inapparent stage of disease. Variation was characterized by point mutations in each SU variable region as well as deletion/insertions within the principal neutralizing domain (PND). Genotypes representative of predominant PND variants were used to construct chimeric proviral clones for virus neutralization assays. A type-specific virus neutralizing antibody response was associated with resolution of acute disease. Variants predominant at later stages of disease showed increasing resistance to both type- and group-specific neutralizing antibody. Variants most resistant to group-specific antibody showed reduced replication fitness in vitro. These studies provide evidence that neutralizing antibody selects for resistant SU variants and thereby plays an important role in immune control of virus replication during the inapparent stage of disease.
Evolution is the study of how variation alters the phenotype and population dynamics over time. Population genetics theories fit viral evolution well because of the properties of a viral population. Retroviruses are characterized by a high mutation and replication rate, which produces a heterogeneous mixture of viral variants commonly referred to as a quasispecies. Equine infectious anemia virus (EIAV) infection is a well-studied model for retrovirus variation and evolution (32, 33, 34). EIAV infection is characterized by a rapid, variable, dynamic disease course. Dynamic features of clinical disease as well as the ability of the horse to control the infection makes EIAV an excellent system to study evolution of viral quasispecies during progression of clinical disease. Here, we describe analyses of genetic data from longitudinal studies of genetic variation in a horse experimentally infected with equine infectious anemia virus. These studies include the genes encoding the regulatory protein Rev and the surface envelope glycoprotein, SU.
Equine infectious anemia virus (EIAV) exhibits a high rate of genetic variation in vivo and results in a clinically variable disease in infected horses. Previous studies identified distinct subpopulations within the Rev quasispecies of an experimentally infected pony, pony 524. The subpopulations showed significantly different phenotypes, as measured by in vitro assays, and fluctuated in dominance in a manner coincident with clinical stage of disease. This study further characterizes the genotypic and phenotypic variation within and between the previously identified EIAV Rev subpopulations in pony 524, and characterizes the EIAV Rev quasispecies of another EIAV-infected pony, pony 625. Within pony 524, the Rev protein was highly conserved and only ten amino acid mutations were found at high frequency within the entire Rev quasispecies. Nine of these amino acid mutations were capable of significantly altering Rev activity, either as a single mutation in the context of the founder variant, R1, or in the context of cumulatively fixed mutations. Phylogenetic analysis indicated nine of these ten mutations were fixed into the high Rev activity subpopulation over the course of disease. The fixation of the amino acid mutations, however, did not confer an increase in Rev activity over time; rather, it maintained the high Rev phenotype of this subpopulation. Greater differences in Rev phenotype were observed between subpopulations, rather than within subpopulations of EIAV Rev as they evolved throughout disease. The greatest difference in Rev phenotype was observed between the two subpopulations of EIAV Rev early in disease, and both subpopulations maintained their respective Rev phenotype throughout disease. The characterization of the Rev quasispecies in pony 625 identified two coexisting subpopulations that differed in phenotype, as observed in pony 524. This provides further evidence that viral quasispecies are composed of coexisting, independently evolving subpopulations that differ in phenotype. The persistence of minor, less fit subpopulations would allow the viral quasispecies to quickly adapt to changes within its environment through the expansion of minor subpopulations. Further study of multiple coexisting subpopulations will provide additional insight into the nature of quasispecies evolution and lentiviral persistence.
These two quasispecies populations differed in their pattern of evolution, with one population accumulating changes in a linear, time-dependent manner, while the other population evolved radially from a common variant. Changes in the population size of the two Rev quasispecies coincided with changes in the clinical stages of disease. Rev variants from each population were biologically tested, and significant differences in Rev activity were detected between the two populations. Together, these results suggested that the distinct Rev populations differed in selective advantage. A statistical correlation was found between Rev quasispecies activity and temperature of the pony over the course of infection. Furthermore, the Rev quasispecies activity differed significantly between different stages of clinical disease. This study suggests that distinct quasispecies populations, which differed in pattern of evolution and niche advantage, co-existed during long term persistent infection by EIAV. A multi-population quasispecies model challenges our current thinking of viral populations and may have significant biological implications.
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