Poliovirus Host Range Is Determined by a Short Amino Acid Sequence in Neutralization Antigenic Site I

Abstract

The mouse-adapted strain of poliovirus type 2 (Lansing) induces fatal poliomyelitis in mice after intracerebral inoculation, whereas mice inoculated with poliovirus type 1 (Mahoney) show no signs of disease. Previous work indicated that the adaptation to mouse virulence is associated with the viral capsid proteins and that mutations in neutralization antigenic site I of poliovirus reduce neurovirulence of the Lansing strain in mice. The role of antigenic site I in mouse neurovirulence was further explored by constructing an antigenic hybrid virus. Six amino acids in antigenic site I of the Mahoney strain were replaced with a sequence specific for the Lansing strain by using a mutagenesis cartridge. The hybrid virus was neutralized by polyclonal antisera elicited by the type 1 and type 2 strains of poliovirus and by neutralizing monoclonal antibodies directed against antigenic site I of type 2 virus. The hybrid virus induced paralytic disease in mice, an observation demonstrating that a short sequence of amino acids in antigenic site I is an important determinant of poliovirus host range. Antigenic site I may be involved in attachment of poliovirus to cells of the mouse central nervous system.Tissue tropism of viruses and the progression of viral disease in the infected host are determined by several factors. Specific cellular surface molecules that serve as viral receptors play an important role in these events. Another determinant is the genotype of a virus because it affects replication within the cell. Genetic variants of highly virulent viruses Poliovirus, a member of the Picornaviridae, has served as a model system to study the molecular basis of viral pathogenesis, particularly the relationship of genotype and phenotype to neurovirulence and host range (1). Attenuation of poliovirus appears to be caused largely by mutations that impair viral replication within the cell (2, 3). Polioviruses, which occur in three serotypes, are human pathogens that can be propagated only in cultured cells of primate origin because other cell lines do not express a functional receptor molecule (4). Although most poliovirus strains can infect only primates, the Lansing strain of poliovirus type 2 [PV-2(L)] has been adapted to mice (5) and causes fatal paralytic disease when inoculated intracerebrally (6). In contrast, many other poliovirus strains, including type I (Mahoney) [PV-1(M)], although highly neurovirulent in primates including man, are avirulent in mice, even when administered in high doses (7). A molecular genetic analysis of PV-2(L) has revealed that the major determinant or determinants of the mouse-adapted phenotype are contained within the four capsid polypeptides (7). A study of the neurovirulence of neutralization escape mutants of PV-2(L) suggests that the mouse-adapted phenotype is determined by a specific region of VP1 located roughly between amino acids 90 and 105 (8).The known chemical (9) and three-dimensional (10) structures of poliovirus, the results of analyses with neutralizing monoclonal ant...

Characterization of CHAT and Cox Type 1 Live-Attenuated Poliovirus Vaccine Strains

“…Similar mutations have been associated with mouse adaptation (32,45), ability to use mutated receptors (9), and ability to persist in neuroblastoma cells (11) in different Mahoney variants.…”

Antigenic structure of chimeras of type 1 and type 3 poliovirus involving antigenic site 1

“…Chimeras in which the main loop of site 1 of the mouse-adapted Lansing strain of type 2 poliovirus was inserted into the equivalent site of the type 1 strain Mahoney have been reported and render the virus able to replicate in mice (Murray et al, 1988b;Martin et al, 1988).…”

Localization of Genomic Regions Specific for the Attenuated, Mouse-adapted Poliovirus Type 2 Strain W-2

“…Antigenic variants of PV2/Lansing with altered neurovirulence display amino acid changes of VP1 residues 93 to 105, with five out of 14 having changes at position 99 (La Monica et al, 1987b). Insertion of an oligonucleotide cartridge corresponding to amino acids 95 to 102 of PV2/ Lansing into the identical site in PV1/Mahoney (avirulent for mice) resulted in a virus which induced paralytic disease in mice (Martin et al, 1988;Murray et al, 1988). These studies suggest that changes in neutralization site 1 may alter receptor binding and consequently the pathogenicity of the virus for mice.…”

“…PV2/W-2 and PV2/Lansing are the only mouse-adapted poliovirus strains that have been well characterized biologically and, in addition, PV2/Lansing has been cloned and sequenced (Racaniello, 1984;La Monica et al, 1986). Recombination studies have revealed that the PV2/ Lansing capsid region is necessary for mouse intracerebral neurovirulence when compared with the nonmouse-adapted PV1/Mahoney strain (La Monica et al, 1986;Martin et al, 1988;Murray et al, 1988). Rather than using host range to analyse the molecular basis for virulence and attenuation, our general strategy is to compare the two mouse-adapted PV2 strains, Lansing and W-2.…”