Rapid emergence of novel antigenic and genetic variants of equine infectious anemia virus during persistent infection

Abstract

Previous results from our laboratory have demonstrated that equine infectious anemia virus displays structural variations in its surface glycoproteins and RNA genome during passage and chronic infections in experimentally infected Shetland ponies (Montelaro et al., J. Biol. Chem. 259:10539-10544, 1984; Payne et al., J. Gen. Virol. 65:1395-1399, 1984). The present study was undertaken to obtain an antigenic and biochemical characterization of equine infectious anemia virus isolates recovered from an experimentally infected pony during sequential disease episodes, each separated by intervals of only 4 to 8 weeks. The virus isolates could be distinguished antigenically by neutralization assays with serum from the infected pony and by Western blot analysis with a monoclonal antibody against the major surface glycoprotein gp90, thus demonstrating that novel antigenic variants of equine infectious anemia virus predominate during each clinical episode. The respective virion glycoproteins displayed different electrophoretic mobilities on sodium dodecyl sulfate-polyacrylamide gels, indicating structural variation. Tryptic peptide and glycopeptide maps of the viral proteins of each virus isolate revealed biochemical alterations involving amino acid sequence and glycosylation patterns in the virion surface glycoproteins gp90 and gp45. In contrast, no structural variation was observed in the internal viral proteins pp15, p26, and p9 from any of the four virus isolates. Oligonucleotide mapping experiments revealed similar but unique RNase T1-resistant oligonucleotide fingerprints of the RNA genomes of each of the virus isolates. Localization of altered oligonucleotides for one virus isolate placed two of three unique oligonucleotides within the predicted env gene region of the genome, perhaps correlating with the structural variation observed in the envelope glycoproteins. Thus these results support the concept that equine infectious anemia virus is indeed capable of relatively rapid genomic variations during replication, some of which result in altered glycoprotein structures and antigenic variants which are responsible for the unique periodic disease nature observed in persistently infected animals. The findings of envelope specific differences in isolates of visna virus and of human T-cell lymphotropic virus III (acquired immune deficiency syndrome-related virus) suggest that this variation may be a common characteristic of the subfamily Lentivirinae.

The immunopathogenesis of equine infectious anemia virus

“…Quarantine rules were based on epidemiologic and entomologic evidence of mechanical transmission of EIAV by hematophagous insects (Hawkins et al, 1973;Hawkins et al, 1976;Issel et al, 1984;Stein et al, 1942). In the 1970s researchers provided the initial evidence that sequential febrile episodes were associated with the emergence of novel antigenic strains of the virus (McGuire et al, 1987;Payne et al, 1984;Salinovich et al, 1986;Kono et al, 1973). Subsequently EIAV was the first lentivirus in which antigenic variation of neutralization-sensitive epitopes was documented (McGuire et al, 1987;Salinovich et al, 1986;Kono et al, 1973).…”

“…In the 1970s researchers provided the initial evidence that sequential febrile episodes were associated with the emergence of novel antigenic strains of the virus (McGuire et al, 1987;Payne et al, 1984;Salinovich et al, 1986;Kono et al, 1973). Subsequently EIAV was the first lentivirus in which antigenic variation of neutralization-sensitive epitopes was documented (McGuire et al, 1987;Salinovich et al, 1986;Kono et al, 1973). Pathogenesis research revealed that many of the clinical signs of disease were a result of widespread activation of the immune system McGuire et al, 1972).…”

“…Each febrile episode in the chronically infected horse is associated with the emergence of a novel antigenic variant of the virus (McGuire et al, 1987;Payne et al, 1984;Payne et al, 1987b;Salinovich et al, 1986;Kono et al, 1973b). It has been proposed that these novel antigenic variants emerge due to host immune pressure and are temporarily capable of escaping the host immune response (Kono et al, 1973a;Kono et al, 1973b), resulting in periodic febrile episodes.…”

Pathogen evolution within host individuals as a primary cause of senescence

“…Variants of hepatitis A virus isolated from persistently-infected monkey cells were cytophatic (Lemon et al, 1991). The appearance of variants which evade immune surveillance has been reported for visna view of sheep (Stanley et al, 1988) and for equine infectious anaemia virus (Salinovich et al, 1986).…”

“…Virus populations of persistent infections are genetically variable. This has been repeatedly observed since the development of techniques for sequencing nucleic acids; recent examples include parainfluenza virus 3 (Murphy, Dimock & Kang, 1991), hepatitis B virus (Groetzinger & Will, 1992), equine infectious anaemia virus (Salinovich et al, 1986;Alexandersen & Carpenter, 1991), visna virus of sheep (Clements et aL, 1980) and caprine arthritis encephalitis virus (Ellis et aL, 1987). RNA viruses as a whole are so variable, in large part because the infidelity of RNA polymerases yields a high mutation rate, that their populations should not be thought of as comprising a basic type around which some variation occurs, but rather as a mixture of indefinite and constantly changing composition (Domingo et al, 1985).…”