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Background. An 18-month-old boy developed encephalopathy, for which extensive investigation failed to identify an etiology, 6 weeks after stem cell transplant. To exclude a potential infectious cause, we performed high-throughput RNA sequencing on brain biopsy. Methods. RNA-Seq was performed on an Illumina Miseq, generating 20 million paired-end reads. Nonhost data were checked for similarity to known organisms using BLASTx. The full viral genome was sequenced by primer walking. Results. We identified an astrovirus, HAstV-VA1/HMO-C-UK1(a), which was highly divergent from human astrovirus (HAstV 1–8) genotypes, but closely related to VA1/HMO-C astroviruses, including one recovered from a case of fatal encephalitis in an immunosuppressed child. The virus was detected in stool and serum, with highest levels in brain and cerebrospinal fluid (CSF). Immunohistochemistry of the brain biopsy showed positive neuronal staining. A survey of 680 stool and 349 CSF samples identified a related virus in the stool of another immunosuppressed child. Conclusions. The discovery of HAstV-VA1/HMO-C-UK1(a) as the cause of encephalitis in this case provides further evidence that VA1/HMO-C viruses, unlike HAstV 1–8, are neuropathic, particularly in immunocompromised patients, and should be considered in the differential diagnosis of encephalopathy. With a turnaround from sample receipt to result of <1 week, we confirm that RNA-Seq presents a valuable diagnostic tool in unexplained encephalitis.

Shortly after the discovery of human herpesvirus 6 (HHV-6), two distinct variants, HHV-6A and HHV-6B, were identified. In 2012, the International Committee on Taxonomy of Viruses (ICTV) classified HHV-6A and HHV-6B as separate viruses. This review outlines several of the documented epidemiological, biological, and immunological distinctions between HHV-6A and HHV-6B, which support the ICTV classification. The utilization of virus-specific clinical and laboratory assays for distinguishing HHV-6A and HHV-6B is now required for further classification. For clarity in biological and clinical distinctions between HHV-6A and HHV-6B, scientists and physicians are herein urged, where possible, to differentiate carefully between HHV-6A and HHV-6B in all future publications.

We identified a stem cell donor with chromosomally integrated human herpesvirus (HHV)–6 and monitored the recipient for HHV-6 after transplantation. The appearance and subsequent increase in HHV-6 load paralleled engraftment and an increase in white blood cell count. Fluorescent in situ hybridization analysis showed integrated HHV-6 on chromosome band 17p13.3 in the donor and in the recipient after transplantation but not in the recipient before transplantation. The increase in viral load due to the genetic transmission of integrated HHV-6 could have been misinterpreted as substantial active infection and, thus, led to the administration of toxic antiviral therapy. We suggest that the confounding influence of integration be considered in laboratory investigations associating HHV-6 with disease

Human cytomegalovirus (HCMV) infects most of the population worldwide, persisting throughout the host's life in a latent state with periodic episodes of reactivation. While typically asymptomatic, HCMV can cause fatal disease among congenitally infected infants and immunocompromised patients. These clinical issues are compounded by the emergence of antiviral resistance and the absence of an effective vaccine, the development of which is likely complicated by the numerous immune evasins encoded by HCMV to counter the host's adaptive immune responses, a feature that facilitates frequent super-infections. Understanding the evolutionary dynamics of HCMV is essential for the development of effective new drugs and vaccines. By comparing viral genomes from uncultivated or low-passaged clinical samples of diverse origins, we observe evidence of frequent homologous recombination events, both recent and ancient, and no structure of HCMV genetic diversity at the whole-genome scale. Analysis of individual gene-scale loci reveals a striking dichotomy: while most of the genome is highly conserved, recombines essentially freely and has evolved under purifying selection, 21 genes display extreme diversity, structured into distinct genotypes that do not recombine with each other. Most of these hyper-variable genes encode glycoproteins involved in cell entry or escape of host immunity. Evidence that half of them have diverged through episodes of intense positive selection suggests that rapid evolution of hyper-variable loci is likely driven by interactions with host immunity. It appears that this process is enabled by recombination unlinking hyper-variable loci from strongly constrained neighboring sites. It is conceivable that viral mechanisms facilitating super-infection have evolved to promote recombination between diverged genotypes, allowing the virus to continuously diversify at key loci to escape immune detection, while maintaining a genome optimally adapted to its asymptomatic infectious lifecycle.

Human herpesvirus 6 (HHV‐6), a member of the β‐herpesvirinae subfamily, is highly seroprevalent, has a worldwide distribution, and infection usually occurs within the first two years of life. In this age group, HHV‐6 causes febrile illness including exanthem subitum with seizures a recognised complication. The virus is predominantly T lymphotropic although it can infect a variety of cell types in vitro and CD46 has recently been identified as a cellular receptor. The virus persists in the host, with a latent state proposed in monocytes and bone marrow progenitor cells, and chronic infection in salivary glands. The virus is pathogenic in the post transplantation period and may be a cofactor in the progression of HIV disease. The virus has also been associated with multiple sclerosis (MS), with the virus detected in oligodendrocytes particularly in plaque regions. The role of HHV‐6 in MS remains controversial and a more extensive understanding of its neurotropism and association with disease is required. Two variants of HHV‐6 exist (A and B) and comparison of their complete nucleotide sequences shows the genomes to be colinear, with a high degree of homology. Variation in specific regions of the genome is more extensive and probably accounts for biological and pathological differences. Almost exclusively, variant B is associated with febrile illness in childhood and is the predominant variant detected in healthy individuals. The epidemiology of HHV‐6A infection needs to be better defined, although it is significantly less prevalent. Biological, genetic, epidemiological and pathological findings suggest that the two variants are divergent. Copyright © 2000 John Wiley & Sons, Ltd.

Qualitative and competitive-quantitative nested polymerase chain reaction (PCR) assays were developed for human herpesvirus 7 (HHV-7). These assays amplify a DNA sequence encoding part of the HHV-7 homologue of the human herpesvirus 6 (HHV-6) U42 gene. The PCR assays were used to analyze peripheral blood DNA (pbDNA) and saliva from 24 healthy volunteers. The prevalence of HHV-7 in saliva was 96%, with a median virus load of 1.1 × 106 copies/mL. Longitudinal analysis revealed sustained virus load, suggesting continued active viral replication. Analysis of 1 µg of pbDNA showed the prevalence of HHV-7 to be 83%, with a median virus load of 40 copies (267 copies/106 cells). Analysis of sequential pbDNA samples showed individuals to have stable levels of HHV-7 virus load. These data demonstrate persistence of HHV-7 at two distinct sites and provide baseline data allowing comparisons with HHV-7 load in immunocompromised patients.

The aim of this dissertation is three-fold: (i) we construct a natural highly homotopy coherent operad structure on the derivatives of the identity functor on structured ring spectra which can be described as algebras over an operad O in spectra, (ii) we prove that every connected O-algebra has a naturally occurring left action of the derivatives of the identity, and (iii) we show that there is a naturally occurring weak equivalence of highly homotopy coherent operads between the derivatives of the identity on O-algebras and the operad O. Along the way, we introduce the notion of N-colored operads with levels which, by construction, provides a precise algebraic framework for working with and comparing highly homotopy coherent operads, operads, and their algebras. We also show that similar techniques may be used to provide a new description of an operad structure for the Goodwillie derivatives of the identity in spaces and describe an explicit comparison map from spaces to algebras over such operad.

Primary human herpesvirus 6 (HHV-6) and 7 (HHV-7) infections were identified in febrile children by qualitative and quantitative polymerase chain reaction (PCR) assays. Diagnosis was based on the differential detection of viral DNA in peripheral blood mononuclear cells (PBMC), but not in saliva. Six of 41 febrile infants, but none of seven non-febrile controls, were identified with primary infections (three HHV-6, three HHV-7). These children had significantly higher viral loads in PBMC (HHV-6, median 24 213 genomes/106PBMC; HHV-7, median 6 040 000 genomes/106 PBMC) than DNA-aemic, saliva PCR positive children (HHV-6, median 1606 genomes/106 PBMC, p < 0.01; HHV-7, median 7089 genomes/106 PBMC, p < 0.05). Viral DNA was detected in serum by PCR in only 50% of primary infections. All three children with primary HHV-7 infection had febrile convulsions. Thus PCR, including quantitative assays, may identify primary HHV-6 and HHV-7 infections when an appropriate combination of clinical specimens is used.