Human herpesvirus-6B (HHV-6B) is a T lymphotropic β-herpesvirus that is clearly distinct from human herpesvirus-6A (HHV-6A) according to molecular biological features. The International Committee on Taxonomy of Viruses recently classified HHV-6B as a separate species. The primary HHV-6B infection causes exanthem subitum and is sometimes associated with severe encephalopathy. More than 90% of the general population is infected with HHV-6B during childhood, and the virus remains throughout life as a latent infection. HHV-6B reactivation causes encephalitis in immunosuppressed patients. The cellular receptor for HHV-6A entry was identified as human CD46, but the receptor for HHV-6B has not been clear. Here we found that CD134, a member of the TNF receptor superfamily, functions as a specific entry receptor for HHV-6B. A T-cell line that is normally nonpermissive for HHV-6B infection became highly susceptible to infection when CD134 was overexpressed. CD134 was down-regulated in HHV-6B-infected T cells. Soluble CD134 interacted with the HHV-6B glycoprotein complex that serves as a viral ligand for cellular receptor, which inhibited HHV-6B but not HHV-6A infection in target cells. The identification of CD134 as an HHV-6B specific entry receptor provides important insight into understanding HHV-6B entry and its pathogenesis.H uman herpesvirus-6B (HHV-6B) is a T lymphotropic β-herpesvirus (1) and is clearly distinct from human herpesvirus-6A (HHV-6A) according to their genetic and antigenic differences and their cell tropism (2-5). Recently the International Committee on Taxonomy of Viruses classified HHV-6B as a separate species.The primary HHV-6B infection causes exanthem subitum (6) and is sometimes associated with severe encephalopathy, whereas the diseases caused by HHV-6A are still unknown. More than 90% of the general population is infected with HHV-6B during childhood, and the virus remains throughout life as a latent infection (7). HHV-6B reactivation causes encephalitis in immunosuppressed patients. HHV-6B reactivation is also associated with drug-induced hypersensitivity syndrome, and recent studies have suggested that it could be related to the severity of this disease (8, 9).HHV-6A can infect a broader variety of human cells than HHV-6B (10), although the homology between HHV-6A and -6B is almost 90% over their entire genome (11-13). Human CD46 has been shown to be a cellular receptor of , and its viral ligand is a glycoprotein (g) complex made up of viral glycoprotein H (gH)/glycoprotein L (gL)/glycoprotein Q1 (gQ1)/ glycoprotein Q2 (gQ2) (15). However, the HHV-6A gH/gL/gQ1/ gQ2 complex binds to its human cellular receptor, CD46, whereas the corresponding complex of HHV-6B does not bind to it (10, 15). Moreover, anti-CD46 antibody does not block HHV-6B infection into the cells, whereas it does HHV-6A infection, indicating that the cellular receptor exists specific for HHV-6B infection. Because HHV-6B remains as a lifelong latent infection in more than 90% of the population and causes severe disease, it is...

dHuman herpesvirus 6 (HHV-6) is a T-cell-tropic betaherpesvirus. HHV-6 can be classified into two variants, HHV-6 variant A (HHV-6A) and HHV-6B, based on genetic, antigenic, and cell tropisms, although the homology of their entire genomic sequences is nearly 90%. The HHV-6A glycoprotein complex gH/gL/gQ1/gQ2 is a viral ligand that binds to the cellular receptor human CD46. Because gH has 94.3% amino acid identity between the variants, here we examined whether gH from one variant could complement its loss in the other. Recently, we successfully reconstituted HHV-6A from its cloned genome in a bacterial artificial chromosome (BAC) (rHHV-6ABAC). Using this system, we constructed HHV-6ABAC DNA containing the HHV-6B gH (BgH) gene instead of the HHV-6A gH (AgH) gene in Escherichia coli. Recombinant HHV-6ABAC expressing BgH (rHHV-6ABAC-BgH) was successfully reconstituted. In addition, a monoclonal antibody that blocks HHV-6B but not HHV-6A infection neutralized rHHV-6ABAC-BgH but not rHHV-6ABAC. These results indicate that HHV-6B gH can complement the function of HHV-6A gH in the viral infectious cycle.

The varicella-zoster virus (VZV) Oka vaccine strain (vOka) differs from the parental strain (pOka) at several amino acid positions, but the mutations responsible for the attenuation of vOka have not been clearly defined. The ORF0 of vOka carries some of the mutations. Although we found that the ORF0 of both strains was incorporated into virus particles, the C-terminal region of vOka ORF0 was presented on the virion surface and was N-glycosylated, suggesting that the mutation in vOka ORF0 changes it into a novel envelope glycoprotein. In a mutant virus in which pOka ORF0 was replaced by vOka ORF0, the molecular weight of ORF0 was altered, but the plaque size was not. In addition, a pOka recombinant virus lacking the hydrophobic domain of ORF0 grew equally well as the wild-type virus, indicating that the mutation in ORF0 is not by itself sufficient for the attenuation of the vOka virus.

It has been shown that adipose-derived mesenchymal stem cells (AMSCs) can differentiate into adipocytes, chondrocytes and osteoblasts. Several clinical trials have shown the ability of AMSCs to regenerate these differentiated cell types. Age-associated dysregulation of the gastrointestinal (GI) immune system has been well documented. Our previous studies showed that impaired mucosal immunity in the GI tract occurs earlier during agingthan is seen in the systemic compartment. In this study, we examined the potential of AMSCs to restore the GI mucosal immune system in aged mice. Aged (>18 mo old) mice were adoptively transferred with AMSCs. Two weeks later, mice were orally immunized with ovalbumin (OVA) plus cholera toxin (CT) three times at weekly intervals. Seven days after the final immunization, when fecal extract samples and plasma were subjected to OVA- and CT-B-specific ELISA, elevated levels of mucosal secretory IgA (SIgA) and plasma IgG antibody (Ab) responses were noted in aged mouse recipients. Similar results were also seen aged mice which received AMSCs at one year of age. When cytokine production was examined, OVA-stimulated Peyer’s patch CD4+ T cells produced increased levels of IL-4. Further, CD4+ T cells from the lamina propria revealed elevated levels of IL-4 and IFN-γ production. In contrast, aged mice without AMSC transfer showed essentially no OVA- or CT-B-specific mucosal SIgA or plasma IgG Ab or cytokine responses. Of importance, fecal extracts from AMSC transferred aged mice showed neutralization activity to CT intoxication. These results suggest that AMSCs can restore impaired mucosal immunity in the GI tract of aged mice.