Date of Award

1990

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

First Advisor

Ronald C. Montelaro

Abstract

Previous investigations have characterized both the genomic and antigenic variations in equine infectious anemia virus (EIAV) surface glycoproteins that arise during replication of the virus. DNA sequence analyses have defined regions of conserved and variable sequences localized in the EIAV envelope glycoproteins. These studies indicate that EIAV persistence and periodicity of clinical disease result from the relatively rapid evolution of antigenic variants which allows the virus to temporarily circumvent the host immune response. The primary objective of this work is the complete characterization of the immunogenic components of the EIAV env-encoded surface unit (SU) and transmembrane (TM) glycoproteins. These surface glycoproteins have been purified by reverse-phase HPLC and directly sequenced to determine cellular processing events in the generation of these critical immunogens. Synthetic peptides have been synthesized and employed in immune binding assays to correlate equine immune reactivity to various neutralizing, nonneutralizing, conserved and variable epitopes of the SU and TM proteins. Sera from both experimentally and naturally EIAV infected animals were utilized in these studies. The relationship between amino acid sequence variations and the observed differences in protein antigenicity has been evaluated. In addition, selected peptides were employed to follow the evolution of glycoprotein-specific humoral responses during the course of virulent and avirulent EIAV chronic infections. Lastly, protein conformational models based on a battery of predictive algorithms have been developed to aid in the elucidation of structural motifs which may contribute to protein immunogenicity. The results of these studies provide a detailed map of EIAV surface glycoproteins immunogenic properties and localize key antigenic determinants in natural and experimental EIAV persistent infections. Immunodominant conserved regions have been identified which may prove useful as antigens for diagnostic testing and potential subunit vaccine candidates have been elucidated. These studies demonstrate the relevance of EIAV as an animal model system for developing and evaluating lentivirus vaccine strategies, including that of the human immunodeficiency virus (HIV).

Pages

300

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