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Enhanced sensitivity to neutralizing antibodies in a variant of equine infectious anemia virus is linked to amino acid substitutions in the surface unit envelope glycoprotein.

ABSTRACT: Serial passage of the prototype (PR) cell-adapted Wyoming strain of equine infectious anemia virus (EIAV) in fetal donkey dermal (FDD) rather than fetal horse (designated fetal equine kidney [FEK]) cell cultures resulted in the generation of a variant virus strain which produced accelerated cytopathic effects in FDD cells and was 100- to 1,000-fold more sensitive to neutralizing antibodies than its parent. This neutralization-sensitive variant was designated the FDD strain. Although there were differences in glycosylation between the PR and FDD strains, passage of the FDD virus in FEK cells did not reduce its sensitivity to neutralizing antibody. Nucleotide sequencing of the region encoding the surface unit (SU) protein from the FDD strain revealed nine amino acid substitutions compared with the PR strain. Two of these substitutions resulted in changes in the polarity of charge, four caused the introduction of a charged residue, and three had no net change in charge. Nucleotide sequence analysis was extended to the region of the FDD virus genome encoding the extracellular domain of the transmembrane envelope glycoprotein (TM). Unlike the situation with the FDD virus coding region, there were minor variations in nucleotide sequence between individual molecular clones containing this region of the TM gene. Although each clone contained three nucleotide substitutions compared with the PR strain, only one of these was common to all, and this did not affect the amino acid content. Of the remaining two nucleotide substitutions, only one resulted in an amino acid change, and in each case, this change appeared to be conservative. To determine if amino acid substitutions in the SU protein of FDD cell-grown viruses were responsible for the enhanced sensitivity to neutralizing antibodies, chimeric viruses were constructed by using an infectious molecular clone of EIAV. These chimeric viruses contained all of the amino acid substitutions found in the FDD virus strain and were significantly more sensitive to neutralizing antibodies than viruses from the parental (PR) molecular clone. These results demonstrated that sensitivity to neutralizing antibodies in EIAV can be conferred by amino acid residues in the SU protein. However, such amino acid substitutions were not sufficient to enhance cytopathogenicity, as the chimeric viruses did not cause excessive degenererative effects in FDD cells, as was observed with the parental FDD virus strain.

SUBMITTER: Cook RF

PROVIDER: S-EPMC188739 | biostudies-other | 1995 Mar

REPOSITORIES: biostudies-other

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Enhanced sensitivity to neutralizing antibodies in a variant of equine infectious anemia virus is linked to amino acid substitutions in the surface unit envelope glycoprotein.

Cook R F RF Berger S L SL Rushlow K E KE McManus J M JM Cook S J SJ Harrold S S Raabe M L ML Montelaro R C RC Issel C J CJ

Journal of virology 19950301 3

Serial passage of the prototype (PR) cell-adapted Wyoming strain of equine infectious anemia virus (EIAV) in fetal donkey dermal (FDD) rather than fetal horse (designated fetal equine kidney [FEK]) cell cultures resulted in the generation of a variant virus strain which produced accelerated cytopathic effects in FDD cells and was 100- to 1,000-fold more sensitive to neutralizing antibodies than its parent. This neutralization-sensitive variant was designated the FDD strain. Although there were d ...[more]

PMID: 7853482

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Project description:The heavily glycosylated HIV-1 envelope glycoprotein (Env) is the sole viral antigen present at the surface of virions and infected cells, representing the main target for antibody responses. The FDA-approved small molecule temsavir acts as an HIV-1 attachment inhibitor by preventing Env-CD4 interaction. This molecule also stabilizes Env in a prefusion "closed" conformation that is preferentially targeted by several broadly neutralizing antibodies (bNAbs). A recent study showed that an analog of temsavir (BMS-377806) affects the cleavage and addition of complex glycans on Env. In this study, we investigated the impact of temsavir on the overall glycosylation, proteolytic cleavage, cell surface expression, and antigenicity of Env. We found that temsavir impacts Env glycosylation and processing at physiological concentrations. This significantly alters the capacity of several bNAbs to recognize Env present on virions and HIV-1-infected cells. Temsavir treatment also reduces the capacity of bNAbs to eliminate HIV-1-infected cells by antibody-dependent cellular cytotoxicity (ADCC). Consequently, the impact of temsavir on Env glycosylation and antigenicity should be considered for the development of new antibody-based approaches in temsavir-treated individuals. IMPORTANCE FDA-approved fostemsavir, the prodrug for the active moiety small molecule temsavir (GSK 2616713 [formally BMS-626529]), acts as an attachment inhibitor by targeting the HIV-1 envelope (Env) and preventing CD4 interaction. Temsavir also stabilizes Env in its "closed," functional state 1 conformation, which represents an ideal target for broadly neutralizing antibodies (bNAbs). Since these antibodies recognize conformation-dependent epitopes composed of or adjacent to glycans, we evaluated the impact of temsavir treatment on overall Env glycosylation and its influence on bNAb recognition. Our results showed an alteration of Env glycosylation and cleavage by temsavir at physiological concentrations. This significantly modifies the overall antigenicity of Env and therefore reduces the capacity of bNAbs to recognize and eliminate HIV-1-infected cells by ADCC. These findings provide important information for the design of immunotherapies aimed at targeting the viral reservoir in temsavir-treated individuals.

Dataset Information

Enhanced sensitivity to neutralizing antibodies in a variant of equine infectious anemia virus is linked to amino acid substitutions in the surface unit envelope glycoprotein.

Publications

Enhanced sensitivity to neutralizing antibodies in a variant of equine infectious anemia virus is linked to amino acid substitutions in the surface unit envelope glycoprotein.

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