Huai-Ying Zheng

Adenovirus Is a Key Pathogen in Hemorrhagic Cystitis Associated with Bone Marrow Transplantation

Late-onset hemorrhagic cystitis (HC) is a well-known complication of bone marrow transplantation (BMT) that is mainly attributed to infection with BK virus (BKV) and adenovirus (AdV). From 1986 through 1998, 282 patients underwent BMT, and 45 of them developed HC. Urine samples tested positive for AdV in 26 patients, of which 22 showed virus type 11. Among patients who underwent allogeneic BMT, logistic regression analysis revealed acute graft-versus-host disease (grade, > or = 2) to be the most significant predictive factor for HC (P < .0001). In addition, a total of 193 urine samples regularly obtained from 26 consecutive patients who underwent allogeneic BMT were examined for BKV, JC virus (JCV), and AdV by means of polymerase chain reaction. Of patients without HC, approximately 30% of the specimens tested positive for BKV (58 samples) and JCV (55 samples), whereas 5 (3%) tested positive for AdV. Of the 3 samples obtained from patients with HC, the numbers of positive results for BKV, JCV, and AdV were 3, 1, and 1, respectively; the numbers of positive results increased to 14 of 17, 9 of 17, and 10 of 17, respectively, when we added another 14 samples obtained from 14 patients with HC (P < .0001, P = .026, and P < .0001, respectively). In conclusion, there was significant correlation between AdV and HC in the patients we studied.

Age-related urinary excretion of BK polyomavirus by nonimmunocompromised individuals.

ABSTRACT Two polyomaviruses, BK virus (BKV) and JC virus (JCV), are ubiquitous in the human population, generally infecting children asymptomatically and then persisting in renal tissue. It is generally thought that reactivation leads to productive infection for both viruses, with progeny shed in the urine. Several studies have shown that the rate of JC viruria increases with the age of the host, but a systematic approach to examine the shedding of BKV has not been developed. To elucidate the relationship between BK viruria and host age, we obtained urine from donors (healthy volunteers or nonimmunocompromised patients) who were divided into nine age groups, each containing 50 members. A high-sensitivity PCR was used to detect BKV and JCV DNA from urinary samples, and the specificity of amplification was confirmed by sequencing or restriction analysis of the amplified fragments. The rate of BK viruria was relatively low in subjects aged <30 years but gradually increased with age in subjects aged ≥30 years. However, BK viruria was less frequent than JC viruria in adults. The detected BKV isolates were classified into subtypes, and detection rates for individual subtypes were compared among age groups; this analysis showed that viruria of subtypes I (the most prevalent subtype) and IV (the second most prevalent subtype) occurred more frequently in older subjects. Therefore, our results reveal new aspects of BK viruria in nonimmunocompromised individuals.

Evolution of Human Polyomavirus JC: Implications for the Population History of Humans

The polyomavirus JC virus (JCV), the etiological agent of progressive multifocal leukoencephalopathy, is ubiquitous in the human population, infecting children asymptomatically, then persisting in the kidney. The main mode of transmission of JCV is from parents to children through long-term cohabitation. Twelve JCV subtypes that occupy unique domains in Europe, Africa, and Asia have been identified. Here, we attempted to elucidate the evolutionary relationships among JCV strains worldwide using the whole-genome approach with which a highly reliable phylogeny of JCV strains can be reconstructed. Sixty-five complete JCV DNA sequences, derived from various geographical regions and belonging to 11 of the 12 known subtypes, were subjected to phylogenetic analysis using three independent methods: the neighbor-joining, maximum parsimony, and maximum likelihood methods. The trees obtained with these methods consistently indicated that ancestral JCVs were divided into three superclusters, designated as Types A, B, and C. A split in Type A generated two subtypes, EU-a and -b, mainly containing European and Mediterranean strains. The first split in Type B generated Af2 (the major African subtype). Subsequent splits in Type B generated B1-c (a minor European subtype) and all seven Asian subtypes (B1-a, -b, -d, B2, MY, CY, and SC). Type C generated a single subtype (Af1), consisting of strains derived from western Africa. While the present findings provided a basis on which to classify JCV into types or subtypes, they have several implications for the divergence and migration of human populations.

Distribution patterns of BK polyomavirus (BKV) subtypes and subgroups in American, European and Asian populations suggest co-migration of BKV and the human race.

BK polyomavirus (BKV) is ubiquitous in the human population, infecting children asymptomatically and then persisting in the kidney. Based on serological and genotyping methods, BKV isolates worldwide are classified into four subtypes (I-IV), with subtype I prevalent throughout the world, subtype IV prevalent in Asia and part of Europe, and subtypes II and III rare throughout the world. Phylogenetic analyses of complete genome sequences have identified several geographically distinct subgroups of subtypes I and IV. To explain how the geographical distribution patterns of BKV subtypes and subgroups were formed, this study hypothesized that BKV co-migrated with human populations (the co-migration hypothesis), and examined this hypothesis by comparing the BKV subtype and subgroup profiles among two American populations in North-east USA and southern California, two European populations in Finland and Ireland/England, and two Asian populations in Japan and China (both American populations were composed mainly of European Americans). The frequency of subtype I was always the highest throughout the populations, but that of subtype IV was variable among populations. A subgroup of subtype I (I/b-2) was detected primarily in all of the European and American populations, whereas subgroup I/c was predominant in the Asian populations (the observed difference was statistically significant). Additionally, all of the five fully sequenced subtype IV isolates from the American and European populations belonged to subgroup IV/c-2, whereas all subtype IV isolates from the Asian populations belonged to the other subgroups. Collectively, the current findings provide support for the co-migration hypothesis.

Evolution of BK Virus Based on Complete Genome Data

The human polyomavirus BK virus (BKV) is ubiquitous in humans, infecting children asymptomatically. BKV is the only primate polyomavirus that has subtypes (I–IV) distinguishable by immunological reactivity. Nucleotide (nt) variations in a major capsid protein (VP1) gene region (designated the epitope region), probably responsible for antigenic diversity, have been used to classify BKV isolates into subtypes. Here, with all the protein-encoding gene sequences, we attempted to elucidate the evolutionary relationships among 28 BKV isolates belonging to subtypes I, III, and IV (no isolate belonging to subtype II, a minor one, was included). First, using the GTR + Γ + I model, maximum likelihood trees were reconstructed for individual viral genes as well as for concatenated viral genes. On the resultant trees, the 28 BKV isolates were consistently divided into three clades corresponding to subtypes I, III, and IV, although bootstrap probabilities are not always high. Then we used more sophisticated likelihood models, one of which takes account of codon structure, to elucidate the phylogenetic relationships among BKV subtypes, but the phylogeny of the deep branchings remained ambiguous. Furthermore, the possibility of positive selection in the evolution of BKV was examined using the nonsynonymous/synonymous rate ratio as a measure of selection. An analysis based on entire genes could not detect any strong evidence for positive selection, but that based on the epitope region identified a few sites potentially under positive selection (these sites were among those showing subtype linked polymorphisms).

Detection of the archetypal regulatory region of JC virus from the tonsil tissue of patients with tonsillitis and tonsilar hypertrophy

The regulatory regions of JC virus (JCV) DNAs in the brain of patients with progressive multifocal leukoencephalopathy (PML) (designated as PML-type regulatory regions) are hypervariable, whereas those in the urine and renal tissue of individuals without PML have the same basic structure, designated as the archetype. It is thought that JCV strains with the archetypal regulatory region circulate in the human population. Nevertheless, Monaco et al (J Virol 70: 7004–7012, 1996) reported that PML-type regulatory regions occur in human tonsil tissue. The purpose of this study is to confirm their findings. Using nested polymerase chain reaction (PCR), the authors detected the regulatory region of JCV DNA in the tonsil tissue from 14 (44%) of 32 donors with tonsillitis and tonsilar hypertrophy. Sequencing of the detected regulatory regions indicated that they were identical with the archetypal regulatory regions detected previously or, in a few cases, slightly deviated from the archetype. This finding suggests not only that tonsil tissue is the potential site of initial JCV infection but also that archetypal JCV strains circulate in the human population.

An Asian Origin for Subtype IV BK Virus Based on Phylogenetic Analysis

Similarly to other members of the Polyomaviridae family, BK virus (BKV) is thought to have co-evolved with its human host. BKV has four subtypes that are distinguishable by immunological reactivity, with two (subtypes I and IV) being most prevalent in human populations. Subtype I is the major subtype worldwide, whereas subtype IV is prevalent in East Asia and Europe but rare in Africa. The geographic distribution pattern of subtype IV BKV is in apparent disagreement with the hypothesis that BKV co-evolved with humans, since subtype IV rarely occurs in Africa. To elucidate the origin of subtype IV, 53 complete subtype IV sequences derived from East Asians and Europeans were subjected to a detailed phylogenetic analysis using the maximum-likelihood and neighbor-joining methods. We identified six subgroups (a1, a2, b1, b2, c1, and c2) that formed a tree represented by the formula: “(a1, a2), ((b1, b2), (c1, c2)).” Interestingly, we found a close correlation between subtype IV subgroups and population geography; thus, all subgroups except c2 were prevalent in particular East Asian populations, with c2 occurring in both Europe and Northeast Asia. From these findings, we conclude that subtype IV of BKV now prevalent in modern humans is derived from a virus that infected ancestral Asians. We introduce two hypotheses to explain how ancestral Asians became infected with subtype IV BKV.

Asian Genotypes of JC Virus in Japanese-Americans Suggest Familial Transmission

ABSTRACT To examine the mode of JC virus (JCV) transmission, we collected urine samples from second- and third-generation Japanese-Americans in Los Angeles, Calif., whose parents and grandparents were all Japanese. From the urine samples of these Japanese-Americans, we mainly detected two subtypes (CY and MY) of JCV that are predominantly found among native Japanese. This finding provides support for the hypothesis that JCV is transmitted mainly within the family through long-term cohabitation.

JC virus strains indigenous to northeastern Siberians and Canadian Inuits are unique but evolutionally related to those distributed throughout Europe and Mediterranean areas

Human polyomavirus JC virus (JCV) isolates around the world are classified into more than 10 geographically distinct genotypes (designated as subtypes). Evolutionary relationships among JCV subtypes were recently examined, and the following pattern of JCV evolution was indicated. The ancestral JCV first divided into three superclusters, designated Types A, B, and C. A split in Type A generated two subtypes, EU-a and -b, containing mainly European and Mediterranean isolates. The split in Type B generated Af 2 (the major African subtype), Bl-c (a minor European subtype), and various Asian subtypes. Type C generated a single subtype (Afl), consisting of isolates derived from western Africa. In this study, JCV isolates prevalent among northeastern Siberians and Canadian Inuits were evaluated in the context of the above-described pattern of JCV evolution. The Siberian/Arctic JCV isolates were classified as belonging mainly to Type A, based on the result of a preliminary phylogenetic analysis. We then examined, using the whole-genome approach, the phylogenetic relationships among worldwide Type A isolates. In neighbor-joining and maximum-likelihood analyses, Type A JCVs worldwide consistently diverged into three subtypes, EU-a, -b, and -c, with high bootstrap probabilities. EU-c was constructed only by northeastern Siberian isolates, derived mainly from Nanais living in the lower Amur River region, and was shown to have been generated by the first split in Type A. Most Siberian/Arctic isolates derived from Chukchis, Koryaks, and Canadian Inuits formed a distinct cluster within the EU-a subtype, with a high bootstrap probability. Based on the present findings, we discuss ancient human migrations, accompanied by Type A JCVs, across Asia and to Arctic areas of North America.

Subtype IV of the BK polyomavirus is prevalent in East Asia

Summary.BK polyomavirus (BKV) is ubiquitous in human populations, infecting children asymptomatically and then persisting in the kidney. Using either serological or genotyping methods, BKV isolates have been classified into four subtypes (I–IV), with subtype I mainly detected in all countries studied so far. To elucidate the subtype of BKV prevalent in East Asia, we examined BKV-positive urine samples collected from immunocompetent elderly patients in Mongolia, Northeast China, Northwest China, Southeast China, Southwest China, Vietnam and Japan. The 287-bp typing region of the viral genome in each of these samples was PCR-amplified and sequenced, and a phylogenetic tree was constructed. According to the tree, BKV isolates in East Asia were unambiguously classified into subtype I or IV (subtypes II and III were not detected). In Japan, subtype I was mainly detected and subtype IV was rare, whereas in the other regions subtype IV was detected frequently, at rates ranging from 24 to 100%. Thus, East Asia (excluding Japan) is a region in which subtype-IV BKV is prevalent, a finding that requires the view of the geographic distribution of BKV subtypes to be revised. Furthermore, we present evidence that the immunological states of urine donors do not affect the pattern of BKV subtypes.