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6. Newly Identified Human Herpesviruses: HHV-6, HHV-7, and HHV-8

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6. Newly Identified Human Herpesviruses: HHV-6, HHV-7, and HHV-8 6. Newly Identified Human Herpesviruses: HHV-6, HHV-7, and HHV-8 LAURIE T. K RUG, CHONG-GEE TEO, KEIKO TANAKA-TAYA, AND NAOKI INOUE Herpesviruses are enveloped, double-stranded DNA viruses that undergo DNA replication in the nucleus. The unique feature of the herpesviruses is the establishment of life-long latency after primary infection coupled with intermittent reactivation from latency in response to various stimuli and under certain immunological condi- tions. Subfamilies, designation, and disease associations of eight known human herpesviruses (HHVs) are summarized in Table 6.1. In this chap- ter, we describe three of these viruses, HHV-6, HHV-7, and HHV-8, all of which were identified in the past 20 years. These are not newly emerged viruses; rather, they have evolved with humans, stemming from a common herpesvirus ancestor approximately 200 million years ago (McGeoch et al., 2000). The three viruses share many properties with other herpesviruses with respect to virion structure, genetic con- tents, and the temporal pattern of gene expression during the productive replication cycle, and yet each has novel strategies for persisting in par- ticular niches of the host. The NCBI website (www.ncbi.nlm.nih.gov/ genomes/ VIRUSES/10292.html) provides the details of their genome structures and coding contents. The betaherpesviruses HHV-6 and -7 are prevalent in normal populations. HHV-6 is classified into two variants, HHV-6A and -6B, which are closely related but show distinct biological and genetic characteristics (Ablashi et al., 1993). HHV-7 and HHV-6B but not HHV-6A cause roseola infantum (exanthem subitum; ES), a mild childhood illness (Fig. 6.1A). In contrast, the gammaher- pesvirus member HHV-8, also known as Kaposi’s sarcoma–associated herpesvirus (KSHV), is less prevalent in immunocompetent indi- viduals. It is known as the etiologic agent of Kaposi’s sarcoma (KS) 195 196 L.T. Krug et al. Table 6.1. Pathogenic profiles of human herpesviruses (HHVs) Disease association ICTV Commonly Reactivation/ Subfamily Genus name used Primary infection chronic infection Simplexvirus HHV-1 HSV-1 Neonatal infections, oral lesion, encephalitis Alpha HHV-2 HSV-2 Genital lesions, encephalitis Varicellovirus HHV-3 VZV Varicella Zoster Cytomegalovirus HHV-5 HCMV Congenital diseases Multisystem diseases Beta Roseolovirus HHV-6 Exanthem subitum Encephalitis HHV-7 Exanthem subitum Lympho- HHV-4 EBV IM BL, NPC, gastric Gamma cryptovirus carcinoma Rhadinovirus HHV-8 HHV-8/ KS, PEL, MCD KSHV IM, infectious mononucleosis; BL, Burkitt lymphoma; NPC, nasopharyngeal carcinoma; KS, Kaposi’s sarcoma; PEL, primary effusion lymphoma; MCD, multicentric Castleman’s disease. (Fig. 6.1B–1D) and primary effusion lymphoma (PEL). Here we focus mainly on their novel biological properties and relate them to the epidemiology, the pathogenesis, and the clinical manifestations of the diseases they cause. (A) (B) (C) (D) Roseola infantum Kaposi's sarcoma Figure 6.1. Roseola infantum in a child (A). Kaposi’s sarcoma (KS) on the trunk (B), on the palate (C), and behind the ear (D). (Courtesy of Dr. Clifford J. Gunthel, Emory University, Atlanta, Georgia [B, D], and Dr. Tim Hodgson, Eastman Institute of Oral Health Care Sciences, London [C]). 6. Newly Identified Human Herpesviruses 197 6.1. HHV-6 and HHV-7 6.1.1. Biology 6.1.1.1. Cell Tropism and Viral Entry HHV-6 and -7 grow well in stimulated primary T cells in vitro, and several isolates have been adapted for growth in T-cell lines. HHV-6 can also infect fibroblasts, endothelial cells, epithelial cells, and immune cell types, including natural killer (NK) cells, monocyte/macrophages, and dendritic cells (DCs). Reports of HHV-6 infection of neural cell types, including astrocytes, glial precursor cells, and oligodendrocytes are intriguing, because oligodendrocytes are the neural cells responsible for myelin production and are the primary target cells in demyelinating dis- eases such as multiple sclerosis (Lusso et al., 1993; He et al., 1996; Albright et al., 1998; Pauk et al., 2001; Dietrich et al., 2004). HHV-6A is more neurovirulent than HHV-6B (Hall et al., 1998), and it replicates more efficiently in primary oligodendrocytes (De Bolle et al., 2005). HHV-6 and -7 may persist in a wide range of tissues in infected indi- viduals. HHV-6 has been detected in CD4+ lymphocytes (Takahashi et al., 1989) and in monocytes/macrophages (Kondo et al., 2002a) obtained from ES patients. Other tissues include brain, liver, salivary glands, and endothelium. HHV-6 and -7 latently infect early bone marrow progenitor cells to be transmitted longitudinally to cells that differentiate along the committed pathways (Luppi et al., 1999; Mirandola et al., 2000). HHV-7 structural antigens are detectable in the lungs, skin, mammary glands, liver, kidney, and tonsils (Kempf et al., 1998). HHV-6 and -7 are likely transmitted via saliva as they can be isolated from saliva of normal adult individuals (Black et al., 1993; Harnett et al., 1990). The entry of most herpesviruses proceeds in two phases: (i) binding of the virion to the cell surface, mainly to glycosaminoglycans on the plasma membrane, and (ii) membrane fusion between the virion envelope and cell membrane via interactions between viral glycoproteins and cellular receptors. Heparin and heparan sulfate inhibit HHV-6 binding to the cell surface less efficiently than herpes simplex virus type 1 (HSV-1) binding, and treatment of cells with heparitinase and heparinase has little effect on HHV-6 binding (Conti et al., 2000). HHV-7 glycopro- tein B (gB) binds to heparin and heparan sulfate on the cell surface (Secchiero et al., 1997). Both variants of HHV-6 utilize the complement regulator CD46 (membrane cofactor protein) as a receptor for cell–cell fusion and entry into cells (Santoro et al., 1999). All four CD46 isoforms can be used as a receptor. In contrast with measles virus glycoproteins that depend strictly 198 L.T. Krug et al. on the short consensus repeat (SCR) regions 1 and 2 in the extracellular portion of CD46, HHV-6 glycoproteins interact with SCRs 2 and 3 but not SCRs 1 or 4 (Greenstone et al., 2002). Like other herpesviruses, HHV-6 encodes multiple glycoproteins that often form complexes with other viral glycoproteins. gH forms a complex with gL and binds to CD46 (Santoro et al., 2003). The gH–gL complex associates with a third com- ponent, gQ or gO (Mori et al., 2003, 2004). gO is encoded by U47, a posi- tional homolog of human cytomegalovirus (HCMV) gO. gQ, which is unique to HHV-6, is encoded by U100. The U100 products of HHV-6A have been reported to form the gp82–105 complex, which is a major virion component and a target for neutralizing antibodies (Pfeiffer et al., 1995). The HHV-6A gH–gL–gQ complex but not the gH–gL–gO com- plex binds to CD46 (Mori et al., 2004). There are two forms of gQ, gQ1 and gQ2, and the gH–gL–gQ complex contains both forms of gQ to gen- erate a tetrameric complex (Akkapaiboon et al., 2004). The HHV-6A and -6B gO and gQ gene products have much lower intravariant identity than the other glycoproteins, suggesting that gO and gQ may account for the difference in cell tropism. The cellular receptor for HHV-6A and -6B gH–gL–gO complexes has yet to be identified. HHV-7 utilizes CD4 as a component of the receptor for entry and interferes with infection by HIV, which also uses CD4 as a receptor (Lusso et al., 1994). HHV-7 gp65, a positional homolog of HHV-6 gp105 (gQ), binds to heparan sulfate proteoglycans. Antiserum against gp65 neutralizes HHV-7 infection, suggesting that gp65 is involved in the viral entry process (Skrincosky et al., 2000). The HHV-7 glycoprotein that mediates CD4-dependent entry remains unknown. Because some of the cell lines expressing surface CD4 by adenovirus gene transfer do not support HHV-7 replication (Yasukawa et al., 1997) and because the chemokine receptors CXCR4 and CCR5 are the main coreceptors for T lympho- cyte–tropic and macrophage-tropic HIV-1, respectively, the possibility of these molecules being used as coreceptors for HHV-7 has been analyzed. Although HHV-7 downregulates surface expression of CXCR4, anti- CXCR4 treatment does not block infection (Yasukawa et al., 1999a; Zhang et al., 2000). This indicates that HHV-7 infection doesnot require CXCR4. HHV-7 infects CCR5-deficient cells, indicating that CCR5 is also not required for entry (Yasukawa et al., 1999a). Therefore, additional cellular factors for HHV-7 entry remain to be identified. 6.1.1.2. Gene Expression and Replication HHV-6 and -7 share the common features of the herpesvirus lytic replication cycle after entry: (i) HHV-6 and -7 nucleocapsids are trans- 6. Newly Identified Human Herpesviruses 199 ported to nuclear pore complexes, (ii) the viral genomes are released into the nucleoplasm, (iii) the genomes circularize (Severini et al., 2003), (iv) viral genes are expressed in a regulated, temporal cascade (Oster and Hollsberg, 2002), (v) viral genomes replicate, leading to (vi) encapsida- tion, maturation, and egress of progeny virions. Figure 6.2 shows the ultra- structual characteristics of HHV-6B–infected cells and HHV-6B virions. There are two unusual features of HHV-6 and -7 replication. Unlike HCMV, HHV-6 and -7 share a feature of alphaherpesviruses by their encoding of an origin-binding protein (OBP) that plays a key role in recog- nition of the viral lytic origin and initiation of DNA replication processes (Dewhurst et al., 1993; Inoue et al., 1994; Krug et al., 2001b). There is a slight difference in the consensus origin sequence and affinity for binding OBP among HSV-1, HHV-6, and HHV-7 (Inoue and Pellett, 1995; Krug et al., 2001a) but the mechanisms for initiating DNA replication are likely conserved.
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