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PubMed1990

Frequent shedding of human herpesvirus 6 in saliva.

We have previously reported the isolation of HHV-6 from saliva samples. Because these isolations were made in PHA-stimulated lymphocytes from healthy adults, which may occasionally contain endogenous HHV-6, it was desirable to repeat this work using cord blood lymphocytes. In this study 18 isolations of viruses provisionally characterized as HHV-6 were made from 19 saliva samples by centrifugally enhanced inoculation into PHA-stimulated cord blood lymphocytes. HHV-6 was not found in 10 pernasal aspirates, 50 endocervical swabs, or 30 male urethral swabs. It is concluded that HHV-6 is usually present in the saliva of most adults and that this affords a possible explanation of the high infection rate with this virus in young children.

Adult↗

PubMed1998

[Human herpesvirus-6 infection induces IL-10 production in monocytes].

In this report, interleukin 10(IL-10) and other cytokines were evaluated through reverse transcription-polymerase chain reaction (RT-PCR) and sandwich ELISA to explore possible immune pathogenesis of human herpesvirus 6 (HHV-6) infection. The results showed that IL-10 was expressed in HHV-6 infected monocytes. Kinetic studies found that transcription of IL-1 beta, IL-6 and TNF-alpha mRNA decreased with accumulation of IL-10 mRNA. When endogenous IL-10 induced by HHV-6 was blocked using anti-human IL-10 monoclonal antibody, the production and the expression of TNF-alpha, IL-1 beta and IL-6 markedly increased as compared with infection by HHV-6 alone, indicating that endogenous IL-10 inhibited cytokine production at the transcription level in HHV-6 infected monocytes. IL-10 has been shown to suppress Th1 response and down-regulate monocyte/macrophage function. The data from our studies suggest that disturbance of immune function and latent infection resulting from HHV-6 infection might partially contribute to endogenous IL-10 production.

Cells, Cultured↗

PubMed2026

A Patient-Derived iPSC-Based Model Reveals Neural Lineage-Specific Transcription of Endogenous HHV-6B.

BACKGROUND: Endogenous human herpesvirus 6 (eHHV-6), in which the entire viral genome is integrated into human chromosomes, is present in approximately 1% of the population and has been associated with various clinical conditions, including neurological disorders. However, its biological significance remains unclear due to the lack of appropriate experimental models. METHODS: We established a patient-derived induced pluripotent stem cell (iPSC)-based tissue culture model using lymphoblastoid cell lines from individuals with eHHV-6B. iPSCs retaining the integrated viral genome were generated and subsequently differentiated into neural stem cells (NSCs). Viral gene expression was evaluated by RT-qPCR under basal conditions and following chemical stimulation. RESULTS: The integrated HHV-6B genome was transcriptionally silent in iPSCs but exhibited spontaneous low-level expression of the immediate-early gene U90 and the late gene U100 in NSCs. Chemical stimulation further enhanced U90 expression, whereas induction of U100 did not reach statistical significance. These findings indicate preferential activation of early viral transcriptional programs in neural lineage cells. CONCLUSIONS: Neural lineage cells provide a permissive environment for expression of eHHV-6B transcripts. This patient-derived iPSC-based model provides a platform for investigating the biological significance of neural lineage-specific eHHV-6 transcripts and may facilitate interpretation of HHV-6 DNA detection in patients with eHHV-6 by enabling studies of cell type-dependent viral transcription.

endogenous HHV-6↗

PubMed1992

IgG antibodies to human herpesvirus-6 (HHV-6) in Italian people.

Sera from a sample of healthy Italian people were tested in an indirect immunofluorescence assay (IFA) for reactivity to a Human Herpesvirus-6 (HHV-6) strain called CV, isolated from a baby with exanthem subitum (Portolani et al., 1990). Seropositivity values of 83.78%, 92.68% and 63.64% were found in subjects aged 3 months-6 years, 6-18 years and over 18 years respectively. Sera from cordal blood, sera from subjects with evidence of active infection by Cytomegalovirus (CMV) or by Epstein-Barr virus (EBV), sera from seropositive adults to Human Immunodeficiency Virus type 1 (HIV) were also investigated for antibodies to the same HHV-6 strain. Values of antibody incidence and antibody content to HHV-6 in these groups of sera were generally higher than in the other groups. HHV-6 reinfections of both endogenous and exogenous origin and antibody cross-reactivity were considered among the reasons of this increase. HHV-6 seropositivity values in healthy Italian people and in people from different countries were also discussed in the light of the antigenic characteristics of the HHV-6 strains used and of the different test conditions.

Adolescent↗

PubMed1997

Interferon-gamma (IFN-gamma) regulates production of IL-10 and IL-12 in human herpesvirus-6 (HHV-6)-infected monocyte/macrophage lineage.

To determine whether HHV-6 infection induces expression and production of IL-10 and IL-12 in monocytes/macrophages, and to explore the influence of IFN-gamma on cytokine production in HHV-6-infected cells, expression and production of IL-10 and IL-12 were evaluated through reverse transcription-polymerase chain reaction (RT-PCR) and sandwich ELISA. HHV-6 infection induced the expression and the production of IL-10 and IL-12 in monocytes and THP-1 cells. Kinetic study showed that the expression of IL-12 mRNA decreased with accumulation of IL-10 mRNA. Expression and production of IL-12 were markedly increased when anti-human IL-10 MoAbs were added to the cultures, implying that endogenous IL-10 induced by HHV-6 inhibited IL-12 production. Addition of increasing concentrations of IFN-gamma to the cultures of HHV-6-infected cells enhanced the expression of IL-12 gene, while the accumulation of IL-10 mRNA was down-regulated. Determination of protein levels of IL-10 and IL-12 by ELISA also showed that IFN-gamma increased IL-12 and decreased IL-10 production. These results suggest that IFN-gamma regulates the production of IL-10 and IL-12 at transcriptional level mainly through inhibiting endogenous IL-10 production in HHV-6-infected monocyte/macrophage lineage.

Antibodies, Blocking↗

PubMed2007

Brains and peripheral blood mononuclear cells of multiple sclerosis (MS) patients hyperexpress MS-associated retrovirus/HERV-W endogenous retrovirus, but not Human herpesvirus 6.

Multiple sclerosis (MS)-associated retrovirus (MSRV)/HERV-W (human endogenous retrovirus W) and Human herpesvirus 6 (HHV-6) are the two most studied (and discussed) viruses as environmental co-factors that trigger MS immunopathological phenomena. Autopsied brain tissues from MS patients and controls and peripheral blood mononuclear cells (PBMCs) were analysed. Quantitative RT-PCR and PCR with primers specific for MSRV/HERV-W env and pol and HHV-6 U94/rep and DNA-pol were used to determine virus copy numbers. Brain sections were immunostained with HERV-W env-specific monoclonal antibody to detect the viral protein. All brains expressed MSRV/HERV-W env and pol genes. Phylogenetic analysis indicated that cerebral MSRV/HERV-W-related env sequences, plasmatic MSRV, HERV-W and ERVWE1 (syncytin) are related closely. Accumulation of MSRV/HERV-W-specific RNAs was significantly greater in MS brains than in controls (P=0.014 vs healthy controls; P=0.006 vs pathological controls). By immunohistochemistry, no HERV-W env protein was detected in control brains, whereas it was upregulated within MS plaques and correlated with the extent of active demyelination and inflammation. No HHV-6-specific RNAs were detected in brains of MS patients; one healthy control had latent HHV-6 and one pathological control had replicating HHV-6. At the PBMC level, all MS patients expressed MSRV/HERV-W env at higher copy numbers than did controls (P=0.00003). Similar HHV-6 presence was found in MS patients and healthy individuals; only one MS patient had replicating HHV-6. This report, the first to study both MSRV/HERV-W and HHV-6, indicates that MSRV/HERV-W is expressed actively in human brain and activated strongly in MS patients, whilst there are no significant differences between these MS patients and controls for HHV-6 presence/replication at the brain or PBMC level.

Brain↗

PubMed1999

Altered cytokine production after human herpes virus type 6 infection.

Several strategies allow viruses to elude the surveillance of the immune system and to establish persistent infection in the host. One of such mechanisms is the immunosuppression caused by the direct infection and functional impairment of immune cells. Human Herpes virus type 6 (HHV-6) is a typical immunosuppressive agent, as suggested by its tropism for both CD4+ and CD8+ T cells, B cells, monocytes/macrophages, megakaryocytes and NK cells. In this study the production of IL-10 and IL-12 by peripheral blood mononuclear cells (PBMC) was evaluated during HHV-6 infection "in vitro". Our results demonstrate that HHV-6 up-regulates IL-10 production by PBMC. Furthermore, our data suggest that rhIFN gamma addition counteracts the effect of HHV-6 in promoting IL-10 release. To gain more insight into the role of IFN gamma, anti-IFN gamma monoclonal antibodies were added to PBMC stimulated with LPS. Neutralization of endogenous IFN gamma upregulated IL-10 release. Furthermore, HHV-6 infection inhibited IFN gamma release induced by LPS in PBMC. No basal production of IL-12 was found in PBMC. Moreover, HHV-6 infection did not induce IL-12 release by PBMC. On the contrary, IL-12 was detected in the supernatants of PBMC treated with LPS with or without rhIFN gamma. In these experimental conditions the further addition of HHV-6 markedly impaired IL-12 production. Moreover, the neutralization of IL-10 resulted in a significant up-regulation of IL-12. Finally our data suggest that the immunodysregulation induced by HHV-6 could be accounted for by a shift from a Th-1 to a Th-2 type cytokine profile.

Cells, Cultured↗

PubMedDate not supplied

Association of human endogenous retroviruses with multiple sclerosis and possible interactions with herpes viruses.

The hypothesis that human endogenous retroviruses (HERVs) play a role in autoimmune diseases is subject to increasing attention. HERVs represent both putative susceptibility genes and putative pathogenic viruses in the immune-mediated neurological disease multiple sclerosis (MS). Gammaretroviral HERV sequences are found in reverse transcriptase-positive virions produced by cultured mononuclear cells from MS patients, and they have been isolated from MS samples of plasma, serum and CSF, and characterised to some extent at the nucleotide, protein/enzyme, virion and immunogenic level. Two types of sequences, HERV-H and HERV-W, have been reported. No known HERV-H or HERV-W copy contains complete ORFs in all prerequisite genes, although several copies have coding potential, and several such sequences are specifically activated in MS, apparently resulting in the production of complete, competent virions. Increased antibody reactivity to specific Gammaretroviral HERV epitopes is found in MS serum and CSF, and cell-mediated immune responses have also been reported. Further, HERV-encoded proteins can have neuropathogenic effects. The activating factor(s) in the process resulting in protein or virion production may be members of the Herpesviridae. Several herpes viruses, such as HSV-1, VZV, EBV and HHV-6, have been associated with MS pathogenesis, and retroviruses and herpes viruses have complex interactions. The current understanding of HERVs, and specifically the investigations of HERV activation and expression in MS are the major subjects of this review, which also proposes to synergise the herpes and HERV findings, and presents several possible pathogenic mechanisms for HERVs in MS.

Antibodies, Viral↗

PubMed2006

Identification and characterization of U83A viral chemokine, a broad and potent beta-chemokine agonist for human CCRs with unique selectivity and inhibition by spliced isoform.

Leukotropic human herpesvirus 6 (HHV-6) establishes a persistent infection associated with inflammatory diseases and encodes chemokines that could chemoattract leukocytes for infection or inflammation. HHV-6 variant A encodes a distant chemokine homolog, U83A, and a polymorphism promoting a secreted form was identified. U83A and three N-terminal modifications were expressed and purified, and activities were compared with a spliced truncated isoform, U83A-Npep. U83A efficiently and potently induced calcium mobilization in cells expressing single human CCR1, CCR4, CCR6, or CCR8, with EC50 values <10 nM. U83A also induced chemotaxis of Th2-like leukemic cells expressing CCR4 and CCR8. High-affinity binding, 0.4 nM, was demonstrated to CCR1 and CCR5 on monocytic/macrophage cells, and pretreatment with U83A or modified forms could block responses for endogenous ligands. U83A-Npep acted only as antagonist, efficiently blocking binding of CCL3 to CCR1 or CCR5 on differentiated monocytic/macrophage leukemic cells. Furthermore, CCL3 induction of calcium signaling via CCR1 and CCL1 induced chemotaxis via CCR8 in primary human leukocytes was inhibited. Thus, this blocking by the early expressed U83A-Npep could mediate immune evasion before finishing the replicative cycle. However, late in infection, when full-length U83A is made, chemoattraction of CCR1-, CCR4-, CCR5-, CCR6-, and CCR8-bearing monocytic/macrophage, dendritic, and T lymphocyte cells can facilitate dissemination via lytic and latent infection of these cells. This has further implications for neuroinflammatory diseases such as multiple sclerosis, where both cells bearing CCR1/CCR5 plus their ligands, as well as HHV-6A, have been linked. Applications also discussed include novel vaccines/immunotherapeutics for cancer and HIV as well as anti-inflammatories.

Animals↗

PubMed1995

Human herpesvirus 6A ts suppresses both transformation by H-ras and transcription by the H-ras and human immunodeficiency virus type 1 promoters.

Human herpesvirus 6 strain U1102 (HHV-6A) was shown to contain a 1,473-bp functional transformation suppressor gene (ts). ts exhibited 24% identity and 51% similarity to adeno-associated virus type 2 Rep68/78. Like adeno-associated virus type 2 Rep68/78, HHV-6A ts suppressed H-ras transformation of NIH 3T3 cells. Suppression of H-ras transformation was eliminated by translation termination linker mutation at amino acid 25, 125, or 245. These data indicated the importance of the C-terminal portion of the ts protein. H-ras transformation was suppressed by ts only when H-ras was expressed by its endogenous H-ras promoter and not when it was expressed by the heterologous murine osteosarcoma virus long terminal repeat (LTR). Furthermore, ts suppressed chloramphenicol acetyltransferase (CAT) activity when the CAT gene was expressed from the H-ras promoter but not the murine osteosarcoma virus LTR promoter. Taken together, the data showed that ts suppressed H-ras transformation at the level of the H-ras promoter. To further identify the interaction of ts with transcriptional regulatory elements, the human immunodeficiency virus type 1 (HIV-1) LTR was used. This promoter was selected because it has well-defined transcriptional regulatory elements for both basal and activated transcription, because its activity is inhibited by the Rep68/78 gene, and because both HHV-6 and HIV-1 naturally infect CD4+ T cells in vivo and have been shown to infect the same cell in vitro. ts suppressed expression from both wild-type and upstream mutant HIV-1 LTR-CAT constructs. However, downstream HIV-1 TAR mutations reversed ts suppression, indicating that TAR is one of the critical elements involved. The data presented demonstrated that HHV-6A ts functionally suppressed H-ras transformation and HIV-1 LTR expression and thus that it may be useful in future gene therapy.

3T3 Cells↗