Molecular Basis for Escape of Equine Infectious Anemia Virus From Type-Specific Neutralizing Antibody
ACVIM 2008
B.A. Sponseller; R.A. Friedrich; S.K. Clark
College of Veterinary Medicine, Iowa State University
Ames, IA, USA

Equine infectious anemia virus (EIAV) is a lentivirus that causes a lifelong infection of equids. While surveillance efforts have reduced the frequency of disease in the United States, absence of an eradication program requiring testing of all horses results in maintenance of viral reservoirs. It has been estimated that the annual cost of surveillance to horse owners approaches $50 million. Infection with EIAV typically results in recurrent episodes of fever, thrombocytopenia, inappetance and depression during the acute and chronic stages of infection. While EIA is fatal in some animals, most eventually control viremia and become inapparent carriers. A hypervariable region (V3) of the viral envelope surface glycoprotein (SU) contains epitopes recognized by neutralizing antibodies and is termed the Principal Neutralizing Domain (PND). From a pony experimentally infected with the Wyoming wild-type virus, we previously characterized genetic variation within the PND. In addition, we characterized the neutralizing antibody response throughout infection. Using chimeric infectious clones, it was demonstrated that a type-specific antibody response occurred with transition from the acute to the chronic stage of infection. Also, viral escape from the type-specific response was associated with 3 amino acid changes within the PND. In this study, we used site-directed mutagenesis to develop a panel of infectious molecular clones in order to elucidate the molecular basis for escape from the type-specific neutralizing antibody response. We determined that a single, putative asparagine (N)-glycan in the upstream region of the PND conferred resistance to the autologous neutralizing antibody response observed, but that presence of a charged histidine did not contribute to viral escape. N-linked glycans are sugar moieties that are attached to the surface of the viral envelope and aid in cloaking viral epitopes recognized by serum antibodies. Our studies indicated that changes confined to the PND can be sufficient for escape from a type-specific neutralizing antibody response. In addition, viral genotypes derived from other EIAV infected horses that were resistant to neutralization became susceptible with elimination of a single putative N-glycan in the PND. These results suggest that the putative N-glycan located in the upstream region of the EIAV PND is, in fact, glycosylated, and that this site is key to viral resistance to neutralizing antibody. In addition, these results indicate that neutralizing antibody rapidly selects for escape mutants which enhance viral persistence. Ongoing studies within the hypervariable PND are aimed at identifying the epitope(s) shielded by the upstream, putative N-glycan.

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Brett Sponseller

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