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Arvin A, Campadelli-Fiume G, Mocarski E, et al., editors. Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis. Cambridge: Cambridge University Press; 2007.

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Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis.

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Chapter 46HHV-6A, 6B, and 7: pathogenesis, host response, and clinical disease

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Department of Microbiology, Osaka University Graduate School of Medicine, Japan

Human herpesvirus 6(HHV-6) is a human pathogen of emerging clinical significance. HHV-6 was first isolated from patients with lymphoproliferative disorders in 1986 (Salahuddin et al., 1986). HHV-6 isolates are classified into two groups as variants A(HHV-6A) and variant B(HHV-6B) (Schirmer et al., 1991. The two variants are closely related but show consistent differences in biological, immunological, epidemiological, and molecular properties. HHV-6B is the major causative agent of exanthem subitum (ES) (Yamanishi et al., 1988), but no clear disease has yet been associated with HHV-6A.

Human herpesvirus 7 (HHV-7) was isolated in 1990 from a healthy individual whose cells were stimulated with antibody against CD3 and then incubated with interleukin-2 (Frenkel et al., 1990). This virus is one of the causative agents of ES (Tanaka et al., 1994). Therefore, HHV-6 and HHV-7 are also called Roseolovirus. HHV-6 and HHV-7 are ubiquitous, and more than 90% of adults have antibody to both viruses. These viruses have extensive homology and belong to the β-herpesvirus subfamily.

The genome of HHV-6A is 159 321 bp in size, has a base composition of 43% G + C, and contains 119 open reading frames. The overall structure is 143 kb bounded by 8 kb of direct repeats, DRL (left) and DRR (right), containing 0.35 kb of terminal and junctional arrays of human telomere-like simple repeats (Gompels et al., 1995). A total of 115 potential open reading frames (ORFs) were identified within the 161 573-bp contiguous sequence of the entire HHV-6B genome (HST) (Isegawa et al., 1999). The HHV-6B(Z29) genome is 162 114 bp long and is composed of a 144 528-bp unique segment (U) bracketed by 8793-bp direct repeats (DR). The genomic sequence allows prediction of a total of 119 unique open reading frames (ORFs), 9 of which are present only in HHV-6B. The overall nucleotide sequence identity between HHV-6A and HHV-6B is 90%. The most divergent regions are DR and the right end of the unique region, spanning ORFs U86 to U100. These regions have 85 and 72% nucleotide sequence identity, respectively (Dominguez et al., 1999).

Virus entry and establishment of infection

Cell tropism in vitro

HHV-6A and HHV-6B replicate most efficiently in vitro in peripheral blood mononuclear cells (PBMCs) or cord blood lymphocytes (CBL), and several isolates have been adapted to grow efficiently in continuous T-cell lines. HHV-6 replicates in activated CD4 T lymphocytes in vivo. HHV-6A and HHV-6B differ in their capacities to replicate in specific transformed T-lymphocyte cell lines. Of the two most widely used strains of HHV-6A, strain GS is most commonly propagated in the T-cell line HSB-2 and strain U1102 is usually propagated in J JHAN cells. HHV-6B (Z29 or HST) is grown most often in primary lymphocytes and has been adapted for growth in the Molt-3 or MT-4 –T cells line. While T cells are most widely used for propagation of HHV-6A and HHV-6B, cell lines of neural, epithelial, and fibroblastic origin have different levels of permissiveness for HHV-6 growth in vitro. However, none of these cells are in general use for routine propagation of the virus. In patients with dual infection, only HHV-6A persisted in CSF, which suggests that HHV-6A has greater neurotropism (Hall et al., 1998). Furthermore, CD8 T-lymphocytes, gamma/delta T-lymphocytes and natural killer (NK) cells support HHV-6 replication in association with surface expression of CD4 (Lusso et al., 1991a,b, 1995; Hall et al., 1998).

Grivel et al. showed that HHV-6A and HHV-6B replicate in human lymphoid tissue, but have significant differences in effects on cellular viability and immunological phenotype (Grivel et al., 2003). There is productive infection of both CD4+ and CD8+ T-cells, although HHV-6B is markedly less efficient than HHV-6A in targeting CD8+ T-cells. CD46 and CD3 are down-modulated in HHV-6 infected tissues. However CD3 down-modulation is restricted to infected cells, while the loss of CD46 expression is generalized. Thus, the down-modulation of CD46 in HHV-6 negative cells most likely represents an authentic bystander effect. Moreover, HHV-6 infection markedly enhanced the production of CC chemokine RANTES.

In contrast, HHV-7 has a narrow tropism for CD4+ T-cells, associated with infectivity for PHA-stimulated PBMCs, CBLs and in an immature T- cell line SupT1 (Cermelli et al., 1997). Both HHV-6 and HHV-7 induce a cytopathic effect in infected cells which is characterized by ballooning degeneration (Fig. 46.1).

Fig. 46.1. Cytopathic effects of HHV-6A or HHH-7.

Fig. 46.1

Cytopathic effects of HHV-6A or HHH-7. (a) HSB-2 cells were infected with HHV-6A. (b) SupT1 cells were infected with HHV-7.

Cell tropism in vivo

The in vivo host tissue range of HHV-6 is broader than its in vitro host range might suggest and includes lymph nodes, lymphocytes, macrophages and monocytes, kidney tubule endothelial cells, salivary glands, and CNS tissues, where viral gene products have been localized to neurons and oligodendrocytes.

HHV-6 genomes and/or antigens are detetable in lymph nodes of patients with sinus histiocytosis with massive lymphadenopathy (SHML) (Levine et al., 1992), tubular epithelial cells, endothelial cells and histiocytes in kidney (Kurata et al., 1990), salivary glands (Fox et al., 1990), and central nervous system (CNS) tissues, where viral gene products have been localized to neurons and oligodendrocytes (Luppi et al., 1994). HHV-6 is also detected in lesions of Langerhans cell histiocytosis in the syndrome of Langerhans cell histiocytosis (Leahy et al., 1993).

HHV-6 was isolated from CD4+ CD8− and CD3+ CD4+ mature T-lymphocytes but could not be isolated from CD4− CD8+, CD4− CD8−, and CD3− T-cells in the peripheral blood of exanthem subitum patients. HHV-6 predominantly infected CD4+ CD8+, CD4+ CD8-, and CD3+ CD4+ cells with mature phenotypes and rarely infected CD4- CD8+ cells from cord blood mononuclear cells, which suggested a predominant tropism of HHV-6 for mature CD4 T-lymphocytes (Takahashi et al., 1989).

So far, two cell types have been recognized as sites of HHV-7 infection in vivo, including CD4+ T-lymphocytes and epithelial cells of salivary glands (Black et al., 1993). HHV-7 is frequently isolated from saliva of healthy adults (Wyatt and Frenkel, 1992). A recent study showed that cells expressing the HHV-7 structural antigen were also detectable in lungs, skin, and mammary glands. Liver, kidney, and tonsils were also positive, although the number of HHV-7-positive cells was low. Large intestine, spleen, and brain were negative for HHV-7 infection (Kempf et al., 1998).

Entry

HHV-6 is characterized by a broad tropism for human cell types but a narrow range of host species. Santoro et al. (1999) identified human CD46 as the cellular receptor for HHV-6. CD46 is a ubiquitous type 1 glycoprotein expressed on the surfaces of all nucleated human cells (Seya et al., 1990). It was originally purified as a complement (C) regulatory protein; it binds C3b and C4b on host cells to allow factor I-mediated inactivation of these C fragments, and it plays an important role in protecting host cells from autologous C protein (Seya et al., 1990). CD46 is also a cellular receptor for measles virus. Evidence for CD46 receptor activity included (ⅰ) A selective and progressive down-regulation of the surface membrane expression of CD46 in activated human CD4+ T-cells in the course of HHV-6A and HHV-6B infection, (ⅱ) inhibition of HHV-6 infection and associated cell fusion by Mab against CD46 and by soluble CD46, and (ⅲ) non-human cells being rendered susceptible to HHV-6-mediated membrane fusion and HHV-6 entry by expression of CD46. However, the expression of CD46 was not sufficient for HHV-6 fusion and infection in all human cell types, suggesting either that a specific co-receptor is needed or that some cells express an inhibitor of the CD46 receptor activity. Mori et al. (2002) found that HHV-6A, but not HHV-6B can mediate fusion-from-without (FFWO) in a variety of human cells, including Vero cells which are an old world monkey cell line. Chinese hamster ovary (CHO) cells are highly resistant to infection by HHV-6 and cell-cell fusion induced by HHV-6A. However HHV-6A, but not HHV-6B induced cell–cell fusion in CHO cells expressing human CD46 without virus replication. Thus, the induction of cell- cell- fusion in the target cells by HHV-6A requires human CD46. Thus, HHV-6A mediates syncytia formation in target cells expressing human CD46 without associated virus replication. Human CD46 is composed of four short consensus repeats (SCRs), a Ser/Thr(ST)-rich domain, 13-amino-acid sequence of unknown significance (UK), a transmembrane domain, and a cytoplasmic tail (CYT) (Seya et al., 1990). The SCR2, -3 and - 4 of the CD46 ectodomain were essential for the HHV-6A induced cell-cell fusion. Another report indicates that the SCR domains 2 and 3 are required for HHV-6 receptor activity (Greenstone et al., 2002).

The products encoded by the U100 gene of HHV-6A have been reported to form a complex containing polypeptides. The U100 gene complex is a major component of the HHV-6 virion and a target for virus-neutralizing antibodies. The gene has an intron-exon structure, resulting in a highly spliced mRNA transcript, and is unique to HHV-6 and HHV-7 (Pfeiffer et al., 1995; Skrincosky et al., 2001). U100 gene products of HHV-6A are mainly composed of 80- and 78-kDa glycoproteins and furthermore, the 80-kDa gene product is the third glycoprotein component of the gH-gL complex in HHV-6A infected cells (Mori et al., 2003a,b). Based on these characteristics, U100 gene products were designated as glycoprotein Q(gQ). The gH-gL-gQ complex is identified as a viral ligand for human CD46 (Mori et al., 2003a,b). The gH-gL complex alone or gQ alone in a transient expression system were unable to bind to CD46. The interaction with CD46 might require additional associations or modification in HHV-6 infected cells. Santoro et al. showed that gH of HHV-6 is a ligand for human CD46, however gH alone does not bind to CD46, and the interaction between gH and CD46 requires HHV-6 infection (Santoro et al., 2003). Therefore, to date, whether one glycoprotein of the gH–gL–gQ complex binds to CD46 directly or whether the steric conformation of the complex itself is required for the interaction with CD46 is unknown.

The entry of herpes viruses into cells is a complex process that is still incompletely understood. In several cases, it appears to require not only a cellular receptor to interact with the virus attachment protein but also at least one additional molecule to interact with the virus and facilitate penetration. Studies on other herpesviruses have provided indirect evidence of a role for homologue of the gH-gL and gB molecules in membrane fusion. In HHV-6, specific monoclonal antibodies against glycoprotein H (gH) and glycoprotein B (gB) inhibited virus-induced cell fusion event and infection (Foa Tomasi et al., 1991; Mori et al., 2002). Considering the previous reports, it seems likely that the process involves several steps. First, HHV-6 gH-gL-gQ complex binds to CD46 and at the same time, gB binds to an unknown cellular molecule, thereby triggering fusogenic activity. Subsequently, viral envelope glycoproteins, probably gB and gH-gL-gQ may act to induce envelope–cell or cell–cell fusion. gB or gH or both are candidates for the actual fusogenic glycoprotens. HHV-7 infects CD4+ T-lymphocye in vitro. The glycoprotein CD4, a member of the immunoglobulin superfamily, is a critical component of the receptor for HHV-7 (Lusso et al., 1994). A selective and progressive downregulation of the surface membrane expression of CD4 was observed in human CD4+ T-cells in the course of HHV-7 infection. Various murine monoclonal antibodies (MAbs) to CD4 and the recombinant soluble form of human CD4 caused a dose-dependent inhibition of HHV-7 infection in primary CD4+ T-lymphocytes. Moreover, radiolabeled HHV-7 specifically bound to cervical carcinoma cells (HeLa) expressing human CD4. However, HHV-7 can infect cells that do not express detectable CD4. It is likely that other host molecules act as receptors; the need for multiple sequential receptors to enable cell-to-cell migration of the virus in tissues is a well-documented phenomenon in other herpesviruses.

The human immunodeficiency virus type 1 (HIV-1) co-receptors, CXC-chemokine receptor (CXCR)4 and CC-chemokine receptor(CCR)5, have been studied to determine whether they serve similar functions for HHV-6A, HHV-6B and HHV-7. Cells from individuals lacking CCR5 were able to support growth of all three viruses, and these individuals were seropositive for the viruses, indicating that this molecule is not essential for viral replication. HHV-7 infection also causes a progressive loss of the surface CXCR4 in CD4(+) T-cells, accompanied by a reduced intracellular Ca2+ flux and chemotaxis in response to stromal cell-derived factor-1 (SDF-1), the specific CXCR4 ligand. Moreover, CXCR4 is downregulated from the surface of HHV-7-infected T-cells independently of CD4. Because intracellular CXCR4 antigen and mRNA levels are unaffected in productively HHV-7-infected cells, the downregulation of CXCR4 apparently does not involve a transcriptional block (Secchiero et al., 1998). However, another report demonstrates that CXCR4 is not involved in HHV-7 infection. The natural ligand of CXCR4, SDF-1alpha, was not able to inhibit HHV-7 infection in SupT1 cells or in CD8(+) T-cell-depleted peripheral blood mononuclear cells. Also, a specific CXCR4 antagonist with potent antiviral activity against T-tropic HIV strains (50% inhibitory concentration IC(50), 1 to 10 ng/ml), completely failed to inhibit HHV-7 infection (IC(50), >250 μ/ml) (Zhang et al., 2000). Unlike HIV-1, HHV-6 and HHV-7 infections do not require expression of CXCR4 or CCR5, whereas marked down-regulation of CXCR4 is induced by these viruses (Yasukawa et al., 1999).

Two HHV-7 glycoproteins have been identified as being able to bind the cell surface proteoglycans heparan and heparan sulfate (Secchiero et al., 1997a,b; Skrincosky et al., 2001). They are the virion glycoprotein, gB and spliced glycoprotein encoded by U100. Thus, soluble heparin was found to block HHV-7 infection and syncytium formation in the SupT1 cell line. The CD4 antigen is a critical component of the receptor for the T-lymphotropic HHV-7 suggesting that heparin-like molecules also play an important role in the HHV-7-entry process. As described above, gB is one of the HHV-7 envelope proteins involved in the adsorption of virus-to-cell surface proteoglycans (Secchiero et al., 1997a,b). Analysis of the biochemical properties of recombinant gp65, (U100 gene products), also revealed a specific interaction with heparin and heparan sulfate proteoglycans and not with closely related molecules such as N-acetylheparin and de-N-sulfated heparin, suggesting that HHV-7 gp65 may contribute to viral attachment to cell surface proteoglycans (Skrincosky et al., 2001). The products of U100 are targets for complement-independent neutralization.

Envelope glycoproteins for entry process

The genes U39 and U48 of HHV-6 and HHV-7 encode the conserved surface glycoproteins gB and gH, which contribute to virus-cell fusion.

HHV-6 gH forms complexes with glycoprotein L (gL, encoded by U82), resulting in the formation of a gp100 complex (Liu et al., 1993). Recently, gQ (encoded by U100) was shown to be a third component of gH-gL complex in HHV-6 (Mori et al., 2003a,b). This gQ is unique to the genus of HHV-6 and HHV-7. The gQ gene is subject to differential splicing, and a number of enveloped glycoprotein –encoding genes, gQ genes of HHV-6A and –6B demonstrate only 72.1% sequence identity. This glycoprotein may have a role in the differential consequences of HHV-6A and B infections. Along with gB and gH, gQ contains epitopes recognized by variant specific neutralizing antibodies.

An unusual feature of HHV-6 in comparison to other herpesviruses is the lack of viral glycoproteins in the plasma membrane (Cirone et al., 1994). HSB-2 T-lymphoid cells and human cord blood mononuclear cells infected with HHV-6 reveal the presence, in the cell cytoplasm, of annulate lamellae (AL), which are absent in uninfected cells (Cardinali et al., 1998). Viral glycoproteins are stored in newly formed annulate lamellae, which function as a viral glycoprotein storage compartment and as a putative site of O-glycosylation. It is proposed that, during viral morphogenesis, nucleocapsids released from the nucleus have a primary envelope that lacks glycoproteins but, in the cytoplasm, this is removed and replaced by a secondary envelope containing glycoproteins acquired from the annulate lamella. Further modification of glycoproteins by glycosylation during transit through the Golgi apparatus occurs before mature virions are released.

Spread in host, mechanisms of tissue damage

Growth properties

HHV-6 and HHV-7 replication cycles are approximately 3 days in activated CBLs grown in the presence of IL-2or PHA. Even in most permissive systems, the infectious yields are relatively low, commonly ranging from 103 to 105 infectious units per ml. Centrifugal infection increases the infectious titer.

Effects of virus infection on host cells

HHV-6 infection has profound effects on host cells. These lead to the development of the classic cytopathic effect of ballooning and multinucleated giant cells.

In the case of HHV-7, multinucleated giant cells occur, not by fusion of cells into syncytia, but by polyploidization (Secchiero et al., 1998). The giant cells, which represent the hallmark of in vitro HHV-7 infection, arise from single CD4(+) T-cells undergoing a process of polyploidization that is linked to disregulation of cyclin-dependent kinase cdc2 and cyclin B. This leads to an accumulation of cells in the G2to M phase of the cell cycle, with nuclei continuing to reproduce in the absence of cell division (Secchiero et al., 1998).

Several cytokines can be induced by HHV-6 and HHV-7 infection. Interferon-alpha, interleukin 1 beta, and tumor necrosis factor are induced by HHV-6 (Kikuta et al., 1990; Flamand et al., 1991). But, exposure of human macrophages to HHV-6 profoundly impairs their ability to produce IL-12 upon stimulation with IFN-gamma and LPS, providing a novel potential mechanism of HHV-6-mediated immunosuppression (Smith et al., 2003). HHV-6 can infect NK cells and T lymphocytes. HHV-6 and HHV-7 induces IL-15 in human PBMC and increases their NK activity (Flamand et al., 1996; Atedzoe et al., 1997; Gosselin et al., 1999). The induction of NK cell activity by HHV-6 is abrogated by monoclonal antibodies to IL-15 but not by mAbs to other cytokines (IFN-alpha, IFN-gamma, TNF-alpha, TNF-beta, IL-2, IL-12). IL-15 protein synthesis is increased in response to HHV-6, and addition of IL-15 to PBMC cultures is found to severely curtail HHV-6 expression. Taken together, the host responds to HHV-6 and HHV-7 infection by up-regulating IL-15 production, which then results in an enhancement of NK cell activity; this, in turn, may play a major role in the control of the viral infection (Flamand et al., 1996; Atedzoe et al., 1997; Gosselin et al., 1999).

HHV-6 affects HIV-1 infection in a coreceptor- dependent manner, suppressing CCR5-tropic but not CXCR4-tropic HIV-1 replication. HHV-6 increases the production of the CCR5 ligand RANTES CC-chemokine, the most potent HIV-inhibitory CC chemokine, and that exogenous RANTES mimics the effects of HHV-6 on HIV-1, providing a mechanism for the selective blockade of CCR5-tropic HIV-1 (Grivel et al., 2001). HHV6 infection induces de novo synthesis of the RANTES in endothelial cells as well (Caruso et al., 2003).

HHV-6A infection induces cell-surface expression of CD4, which then allows infection by HIV-1 of cells such as gamma/delta T cells that were previously refractile to infection (Lusso et al., 1991a,b, 1995; Caruso et al., 2003). HHV-6A, but not HHV-6B or HHV-7, down-regulates cell surface expression of CD3, and HHV-7 predominantly down-regulates CD4 (Furukawa et al., 1994).

HHV-6A, HHV-6B and HHV-7 were evaluated for their effects on in vitro colony formation of hemopoietic progenitor cells derived from CBLs. Formation of both granulocyte/macrophage and erythroid colonies was suppressed after infection with HHV-6B. Although HHV-6A suppressed the formation of erythroid colonies as efficiently as HHV-6B, HHV-6A did not exhibit significant suppressive effect on the formation of granulocyte/macrophage colonies. HHV-7 had no effect on either lineage (Isomura et al., 1997). Furthermore, the suppressive effects of HHV-6 on thrombopoiesis in vitro was evaluated. Using CBLs as the source of hematopoietic progenitors, two types of colonies, megakaryocyte colony-forming units and non- megakaryocyte colony-forming units colonies, were established. HHV-6A and HHV-6B inhibited thrombopoietin-inducible both megakaryocyte and non-megakaryocyte colony formation. In contrast, HHV-7 had no effect on thrombopoietin-inducible- colony formation (Isomura et al., 2000). More differentiated CD34+ cells, which were a major source of hematopoietic progenitor cells, were more susceptible to the effects of HHV-6, indicating that the targets for hematopoietic suppression by HHV-6 are the differentiated cells (Isomura et al., 2003). In contrast, in bone marrow-derived cells, both HHV-6A and HHV-6B suppressed erythroid, granulocyte-macrophage, and multipotential precursors of the granulocyte, erythrocyte, monocyte, and megakaryocyte lineages (Carrigan and Knox, 1995). The mechanisms of cell death in the human CD4+ T-cell line J JHAN mediated by HHV-6 were investigated (Inoue et al., 1997) by transmission electron microscopy infected cells showed characteristics of apoptosis, such as chromatin condensation and fragmentation of nuclei, but few virus particles were detected in apoptotic cells. Two-color flow cytometric analysis revealed that DNA fragmentation was present predominantly in uninfected cells but not in cells that were productively infected with HHV-6 (Inoue et al., 1997). Acute in vitro HHV-7 infection induced (ⅰ) the formation of giant multinucleated syncytia, which eventually underwent necrotic lysis, and (ⅱ) single-cell apoptosis. Using electron microscopy analysis, all syncytia contained large amounts of virions and most cells within syncytia them exhibited clear evidence of necrosis, whereas apoptosis was predominantly observed in single cells. Although empty viral capsids could be identified in the cytoplasm of approximately 25% of single cells exhibiting an apoptotic morphology, few mature virions were observed in these cells. Thus, it appears that apoptosis occurred predominantly in uninfected bystander cells but not in productively HHV-7-infected cells (Secchiero et al., 1997a,b). Apoptosis induced by HHV-6 in cord blood mononuclear cells (CBMCs) was also investigated. CBMCs prestimulated with phytohemagglutinin (PHA) were infected with HHV-6 and cultured with interleukin 2 (IL-2) for 5 days. The percentage of the hypodiploid fraction by cell cycle analysis and the percentage of cells showing apoptosis determined by terminal deoxytransferase (TdT)- mediated dUTP nick end-labeling (TUNEL) assay were significantly higher in HHV-6-infected CBMC compared with uninfected CBMC. 7A6 antigen, induced on the mitochondria membrane in apoptotic cells, was mainly expressed in CD4+ cells; 7A6 antigen was also detected in HHV-6-infected cells as determined by expression of gH. Thus, HHV-6 induces apoptosis in HHV-6-infected CBMCs different from T-cells lines (Ichimi et al., 1999). In order to confirm that apoptosis of CD4+ T lymphocytes also occurs in HHV-6 infection in vivo, apoptosis of lymphocytes isolated from nine patients with exanthem subitum and from an adult patient with severe HHV-6 infection was examined (Yasukawa et al., 1998). PBMCs were cultured for 3 days and apoptosis of lymphocytes was examined by flow cytometry of propidium iodide-stained DNA. The percentages of hypodiploid DNA, indicating apoptosis, in lymphocytes from 10 patients with HHV-6 infection were significantly higher than those from five infant patients with noninfectious diseases and five healthy adults (P < 0–0002). DNA fragmentation was also detected in lymphocytes from patients with HHV-6 infection. Apoptosis appears to occur predominantly in CD4+ T-lymphocytes and HHV-6 is isolated from the CD4+ T lymphocyte fraction (Yasukawa et al., 1998).

Accordingly, in CBLs, infected cells are apoptotic, while in transformed cells, infected cells die by necrotic lysis and apoptosis is triggered in non-productively infected cells. The latter observation suggests that the virus may be able to inhibit apoptosis in at least some cells and that its replication might be enhanced by suppression of apoptosis.

To dissect the underlying molecular events, the role of death-inducing ligands belonging to the tumor necrosis factor (TNF) cytokine superfamily was investigated (Secchiero et al., 2001a,b). HHV-7 selectively up-regulated the expression of TNF-related apoptosis-inducing ligand (TRAIL), but not that of CD95 ligand or TNF-alpha in SupT1 or primary activated CD4(+) T-cells. Moreover, in a cell-to-cell-contact assay, HHV-7-infected CD4(+) T-lymphocytes were cytotoxic for bystander uninfected CD4(+) T-cells through the TRAIL pathway. By contrast, HHV-7 infection caused a marked decrease of surface TRAIL-R1, but not of TRAIL-R2, CD95, TNF-R1, or TNF-R2. Of note, the down-regulation of TRAIL-R1 selectively occurred in cells coexpressing HHV-7 antigens that became resistant to TRAIL-mediated cytotoxicity. These data suggest that the TRAIL-mediated induction of T-cell death may represent an important immune evasion mechanism of HHV-7, helping the virus to persist in the host organism throughout its lifetime (Secchiero et al., 2001a,b).

Disease consequences

Clinical features in hosts

Primary infection

Both HHV-6 and HHV-7 are ubiquitous viruses, and infection occurs during infancy. HHV-6B is a causative agent of ES (Yamanishi et al., 1988). In most cases, ES is benign; it is associated with other symptoms including diarrhea, cough, lymph node swelling as bulging fontanel. ES is a common disease of infants all over the world. Typically, the infant gets sudden fever, which lasts for a few days, and a rash appears on the trunk and face and spreads to the lower extremities as the fever subsides. In adults, primary infections can cause mononucleosis like disease and hemophagocytic syndrome (Akashi et al., 1993). HHV-7 can also cause ES and was isolated from PBMCs of a infant with typical ES (Tanaka et al., 1994). The median age of children with primary HHV-7 infection was 26 months, which is significantly older than that of children with primary HHV-6 infection (median, 9 months).

Immune response during primary infection

The early immune response was studied by assessing interferon (IFN) and natural killer cell activity in 13 patients with ES associated with HHV-6 infection during the acute and convalescent phases (Takahashi et al., 1992). Only IFN-alpha was significantly increased in the plasma of patients during the acute febrile phase compared with the convalescent period. The inhibitory effect of IFN-alpha and IFN-beta on HHV-6 replication was demonstrated in vitro with cord blood mononuclear cells. Natural killer cell activity was also significantly augmented in the acute phase, especially in the exanthem period, compared to in the convalescent phase. These results suggest that the enhanced IFN-alpha response and natural killer cell activity in the acute early phase of the disease may play pivotal roles in the recovery from ES.

Other symptoms associated with primary HHV-6 and 7 infection

The primary infection by HHV-6 and HHV-7 can cause a highly febrile illness in childhood, complicated by seizures (Torigoe et al., 1996). Cases of possible HHV-6-associated encephalitis in young children have been reported (Asano et al., 1992). Self-limited involvement of the central nervous system (CNS) is a relatively common complication of primary infection with HHV-6 in normal children. Liver dysfunction (Asano et al., 1990; Tajiri et al., 1990), idiopathic thrombocytopenic purpura (Yoshikawa et al., 1993) are also associated with HHV-6 infection.

Reactivation of HHV-6 and its clinical symptoms

Since HHV-6 and HHV-7 establish latency following primary infection, they are important pathogens in immunocompromised hosts. Reactivation of HHV-6 and HHV-7 ocurres in patients after bone marrow transplantation, solid organ transplantation such as liver, renal and heart transplantation, and AIDS.

Bone marrow transplantation (BMT)

Asymptomatic HHV-6 reactivations appear to be common following allogeneic BMT (Cone et al., 1999), but HHV-6 reactivation associated with symptoms such as bone marrow suppression, encephalitis (Drobyski et al., 1994; Tsujimura et al., 1998; Rodrigues, 1999), pneumonitis (Cone et al., 1993) and acute graft-versus-host disease (GVHD) in BMT recipients has also been recognized. Idiopathic marrow suppression occurred frequently in patients with concurrent HHV-6 viremia (Drobyski et al., 1993). Infection with HHV-6 has been correlated with the development of skin rashes. HHV-6 DNA was detected in skin and/or rectal biopsies more frequently in allogeneic recipients with severe GVHD (92%) than in those with either moderate (55%) or mild GVHD (22%), suggesting that the presence of HHV-6 DNA in the skin or rectum may be a factor in determining GVHD severity (Appleton et al., 1995).

Solid organ transplantation

HHV-6 infection after liver transplantation is associated with an immunosuppressive state (Singh et al., 1995, 2002a,b). Acute febrile illness characterized by life-threatening thrombocytopenia, progressive encephalopathy and skin rash occurred with invasive HHV-6 infection in a liver transplant recipient (Singh et al., 1995). Prolonged suppression of the HHV-6 memory response, but not overall T-helper cell function was documented and may play a role in the pathogenesis of HHV-6 infection in liver transplant recipients (Singh et al., 2002a,b). The memory response to CMV after liver transplantation was significantly more robust than to HHV-6 (Singh et al., 2002a,b). Griffiths et al. conducted a prospective study of the possible relationship of HHV-6 and HHV-7 infection with clinical symptoms after liver transplantation (Griffiths et al., 1999). Although the virus load for HCMV was significantly greater than that for HHV-6 or HHV-7, HHV-6 and HHV-7 may be the cause of some episodes of hepatitis and pyrexia (Griffiths et al., 1999). HHV-6 and CMV are significantly and independently associated with biopsy-proven graft rejection after liver transplantation (Griffiths et al., 2000).

AIDS

Reactivation of HHV-6 has been reported to be possibly associated with interstitial pneumonia, encephalitis, and retinal disorder in AIDS patients, but specific clinical syndromes associated with reactivation are rare.

The other possible associated diseases

Multiple sclerosis (MS)

Several studies have suggested an association between HHV-6 and MS (Challoner et al., 1995; Soldan et al., 1997). However, negative results were also seen in other reports (Coates and Bell, 1998). There was no significant difference between MS patients and non-MS-patients by staining brains immunocytochemically (Coates and Bell, 1998). Therefore, whether HHV-6 contributes to MS pathogenesis in unclear.

Drug hypersensitivity

Drug-induced hypersensitivity syndrome is characterized by a severe, potentially fatal, multi organ hypersensitivity reaction that usually appears after prolonged exposure to certain drugs. Its delayed onset and clinical resemblance to infectious mononucleosis suggest that underlying viral infections may trigger and activate the disease in susceptible individuals receiving these drugs. Reactivation of HHV-6, possibly in concert with HHV-7 may contribute to the development of a severe drug-induced hypersensitivity syndrome (Suzuki et al., 1998; Tohyama et al., 1998).

References

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