Poliovirus selectively replicates in neurons in the spinal cord and brainstem, although poliovirus receptor (PVR) expression is observed in both the target and nontarget tissues in humans and transgenic mice expressing human PVR (PVR-transgenic mice). We assessed the role of alpha/beta interferon (IFN) in determining tissue tropism by comparing the pathogenesis of the virulent Mahoney strain in PVR-transgenic mice and PVR-transgenic mice deficient in the alpha/beta IFN receptor gene (PVR-transgenic/Ifnar knockout mice). PVR-transgenic/Ifnar knockout mice showed increased susceptibility to poliovirus. After intravenous inoculation, severe lesions positive for the poliovirus antigen were detected in the liver, spleen, and pancreas in addition to the central nervous system. These results suggest that the alpha/beta IFN system plays an important role in determining tissue tropism by protecting nontarget tissues that are potentially susceptible to infection. We subsequently examined the expression of IFN and IFN-stimulated genes (ISGs) in the PVR-transgenic mice. In the nontarget tissues, ISGs were expressed even in the noninfected state, and the expression level increased soon after poliovirus infection. On the contrary, in the target tissues, ISG expression was low in the noninfected state and sufficient response after poliovirus infection was not observed. The results suggest that the unequal IFN response is one of the important determinants for the differential susceptibility of tissues to poliovirus. We consider that poliovirus replication was observed in the nontarget tissues of PVR-transgenic/Ifnar knockout mice because the IFN response was null in all tissues.

We analyzed variations in long (L)- and middle (M)-wavelength-sensitive opsin gene loci in crab-eating monkeys. Unlike humans, most monkeys have a single L and a single M gene. Two variant genotypes, one with only one opsin gene (dichromatic) and one with tandemly arrayed multiple genes, were also found in the monkeys. However, the frequency of the former was 0.47%, and that of the latter was 5% in the monkeys, while 2% and 66%, respectively, in Caucasian males. The two variants were found only in Java Island, Indonesia, and South Thailand, respectively. The data suggest that the frequency of each genotype is different among Old World primates.

Replication of poliovirus (PV) is (7) found that monkey kidney developed permissivity to infection after cultivation in vitro and that PV titers could be quantified by plaque assay. PV, therefore, is able to replicate in monolayer cells in primary culture and in cell lines derived from almost any tissue of primates, although PV cannot replicate well in the extraneural tissues in vivo. This new technology for propagating PV in cell cultures in vitro had a great impact on virology and allowed revolutionary progress in PV studies. Attenuated Sabin strains were developed by a number of passages of virulent PV strains in cultured cells (53). Large-scale production of PV vaccines has been done using monkey kidney cells. The molecular mechanisms of PV replication have been studied using cultured cells with strict control of the experimental conditions (49). Although we have benefited greatly from this, the molecular basis for this paradoxical change in susceptibility is still unknown.The factors that control PV susceptibility have been studied. The research focused on identifying the determinants of tissue and cell tropism. Holland and colleagues thought that susceptibility was determined at the level of virus entry into the cell. They proposed that the PV receptor (PVR) is a major determinant of tissue and cell tropism based on observations that a single round of replication occurred in nonpermissive mouse cells after transfection of PV genomic RNA (20) and that PV was adsorbed by a homogenate of neural tissues (19). Molecular cloning of the human PVR gene revealed that PVR is a membrane protein that belongs to the immunoglobulin superfamily (29,40). Transgenic (tg) mice that carry the human PVR gene were produced. PV selectively replicated in the central nervous system (CNS), and the mice showed paralytic disease that resembled human poliomyelitis upon PV infection (31, 51). If Holland's hypothesis were correct, one could expect that PVR would not be expressed in the extraneural tissues at high levels in vivo but would be expressed in the cells after cultivation in vitro. However, PVR mRNA was detected in various tissues of human and PVR-tg mice (43). Furthermore, when Ren and Racaniello (50) investigated the distribution of PVR

The host range of most poliovirus (PV) strains is restricted to simians. This host range specificity is believed to be determined by the interaction between PV and its receptor molecule. To elucidate the molecular basis of this species-specific infection of PV, we cloned orthologs of the PV receptor (PVR) gene ( pvr) as well as those of PV receptor-related genes 1 and 2 ( prr1 and prr2) from various mammalian species. These three genes are widely present in mammalian genomes including those of non-susceptible species. Comparison of the deduced amino acid sequences of PVR orthologs revealed that the NH(2)-terminal immunoglobulin-like domain (domain 1), which is the virus binding site in the human PVR, is highly variable among species, whereas that of PRR1 is highly conserved. Domain 1 of the PVR orthologs for the ring-tailed lemur and rabbit, which are not susceptible to PV, show only 51 and 61% amino acid sequence identity to that of human PVR, respectively. Chimeric PVR proteins that have the domain 1 of the ring-tailed lemur and rabbit PVRs failed to serve as receptors for PV. These results suggest that rapid changes in the domain 1 sequence during mammalian evolution determined the host range restriction of PV.