New sequence polymorphisms in the outer loops of the JC polyomavirus major capsid protein (VP1) possibly associated with progressive multifocal leukoencephalopathy

Abstract

JC polyomavirus (JCPyV) causes progressive multifocal leukoencephalopathy (PML) in patients with decreased immune competence. To elucidate genetic changes in JCPyV associated with the pathogenesis of PML, multiple complete JCPyV DNA clones originating from the brains of three PML cases were established and sequenced. Although unique rearranged control regions occurred in all clones, a low level of nucleotide variation was also found in the coding region. In each case, a parental coding sequence was identified, from which variant coding sequences with nucleotide substitutions would have been generated. A comparison between the parental and variant coding sequences demonstrated that all 12 detected nucleotide substitutions gave rise to amino acid changes. Interestingly, seven of these changes were located in the surface loops of the major capsid protein (VP1). Finally, 16 reported VP1 sequences of PML-type JCPyV (i.e. derived from the brain or cerebrospinal fluid of PML patients) were compared with their genotypic prototypes, generated as consensus sequences of representative archetypal isolates belonging to the same genotypes; 13 VP1 proteins had amino acid changes in the surface loops. In contrast, VP1 proteins from isolates from the urine of immunocompetent and immunosuppressed patients rarely underwent mutations in the VP1 loops. The present findings suggest that PML-type JCPyV frequently undergoes amino acid substitutions in the VP1 loops. These polymorphisms should serve as a new marker for the identification of JCPyV isolates associated with PML. The biological significance of these mutations, however, remains unclear.

Naturally Arising Strains of Polyomaviruses with Severely Attenuated MicroRNA Expression

“…All three polyomaviral miRNA attenuated/null polyomaviruses that we have identified likely arose during infections of immunocompromised hosts ( Table 2). The JCPyV strain Seq 3-5 was detected in the cerebral spinal fluid of a severely immunocompromised patient suffering from progressive multifocal leukoencephalopathy (PML) (43). Seq 3-5 arose from a 6-bp insertion within the 3p arm of the pre-miRNA genomic region.…”

“…The sequences of JCV and SV40 strains analyzed were obtained from previously published reports (41)(42)(43). The pre-miRNA regions corresponding to nucleotide positions 2766 to 2930 of the SV40 reference strain, 776, and nucleotide positions 2641 to 2808 of the JCV reference strain, Mad1, were used to construct the respective phylogenetic tree.…”

“…From this analysis, two strains were identified, both variants of JCPyV (Table 1). Both JCPyV strains HWM and Seq 3-5 were isolated from severely immunosuppressed hosts (42,43). Seq 3-5 contains two point mutations mapping to the terminal loop region and a 6-bp duplication mapping to the 3p mature miRNA portion of the pre-miRNA.…”

The human JC polyomavirus (JCPyV): virological background and clinical implications

“…Preliminary data examining the association of HLA class I antigens and PML reported in HIV-infected Caucasian PML patients showed a decreased frequency of HLA-A3, an increased frequency of HLA-B18, and a decreased frequency of HLA-A68 among PML survivors, although statistical significance was not reached after Bonferroni correction for multiple testing (20). However, two viral markers of PML pathology have been described largely independently of the JCPyV genotype: First, a set of point mutations affecting the sialic acid binding pocket of VP1 (21)(22)(23)(24); and second, diverse unique sequence rearrangements of the NCCR that are thought to be derived from the linear archetype (at-) NCCR (13,(25)(26)(27)(28).…”

JC Virus Variant Associated with Cerebellar Atrophy in a Patient with AIDS

“…The factors involved in the development of JCV-associated neuronal disorders are poorly understood. In patients with PML, sequence variations in the JC virus capsid protein VP1 and in the regulatory region (RR) which regulates early and late viral gene expression have been shown to occur in cerebral JCV isolates (7,14,17,18,19). Viral characteristics associated with JCV cerebellar disorders remain to be explored.…”