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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., . 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.

The human β-herpesvirus subfamily consists of human cytomegalovirus (HCMV), human herpesvirus 6 (HHV-6), and human herpesvirus 7 (HHV-7). HHV-6 and HHV-7 belong to the Roseolovirus genus of the β-herpesviruses, and the HHV-6 species are divided into two variants: HHV-6A and HHV-6B. These viruses establish a lifelong infection of their host, reactivate frequently, and reactivated viruses are shed into the saliva (Jordan, ; Krueger et al., 1990). Some evidence suggests that the molecular mechanisms of viral latency and reactivation are shared among these viruses. HHV-6B is reactivated from latency after coinfection with HHV-7 (Katsafanas et al., 1996), and HCMV disease is frequently associated with concurrent HHV-6 and HHV-7 reactivation in transplant patients (Lautenschlager et al., ; Mendez et al., 2001)

This comprehensive account of the human herpesviruses provides an encyclopedic overview of their basic virology and clinical manifestations. This group of viruses includes human simplex type 1 and 2, Epstein–Barr virus, Kaposi's Sarcoma-associated herpesvirus, cytomegalovirus, HHV6A, 6B and 7, and varicella-zoster virus. The viral diseases and cancers they cause are significant and often recurrent. Their prevalence in the developed world accounts for a major burden of disease, and as a result there is a great deal of research into the pathophysiology of infection and immunobiology. Another important area covered within this volume concerns antiviral therapy and the development of vaccines. All these aspects are covered in depth, both scientifically and in terms of clinical guidelines for patient care. The text is illustrated generously throughout and is fully referenced to the latest research and developments.

Herpes simplex virus (HSV) represents the most comprehensive example of virus-receptor interaction in the Herpesviridae family, and the prototype virus encoding multipartite entry genes. Whereas small enveloped viruses package the functions required for entry and fusion into one or two fusion glycoproteins, in HSV the same functions are distributed over several distinct glycoproteins, each with a specialized activity. In addition, HSV encodes a highly sophisticated system for promoting and blocking fusion between the viral envelope and cell membrane. Because the most obvious models of virus entry into the cell do not fit with the HSV complexity, and despite our detailed knowledge of the HSV receptors and of the crystal structure of glycoprotein D (gD), the receptor-binding glycoprotein, and of gB, HSV entry is still, in part, a puzzle (WuDunn and Spear, ; Cocchi et al., ; Geraghty et al., ; Carfi et al., 2001).

A commonly accepted concept in herpesvirology holds that herpesvirions are formed by budding of nucleocapsids at the inner nuclear membrane and the enveloped virions are released into the perinuclear space (see Chapter 13). This is a closed compartment that virions need to exit, in order to reach the extracellular space and start a new infection cycle. How alphaherpesviruses accomplish this goal is a controversial issue. Of the two pathways of virus exit proposed, the single envelopment and the double envelopment, also referred to as de-envelopment–re-envelopment, each has evidence and supporters in the literature (the topic has been covered in excellent reviews and papers (Enquist et al., ; Skepper et al., ; Johnson and Huber, ; Mettenleiter, 2002). Part of the uncertainties that still dominate this topic comes from the difficulties in interpreting static electron microscopy images. Thus cytoplasmic virions juxtaposed to curved vesicles were interpreted in some studies as budding virions, i.e., as evidence for secondary envelopment and for the deenvelopment-reenvelopment pathway. In other studies they were interpreted as virions undergoing fusion with encasing vesicles, i.e., as evidence of de-envelopment (Campadelli-Fiume et al, : Roizman and Knipe, 2001). To solve these ambiguities, several approaches have been undertaken in recent years, including the generation of genetically modified mutants and cytochemistry.

Despite biological divergence, human cytomegalovirus (HCMV, HHV-5), on the one hand, and the three human roseolaviruses (HHV-6A, HHV-6B, HHV-7), on the other hand, share approximately 70 evolutionarily conserved and collinear genes (italics, Table 15.1). Mammalian betaherpesviruses probably have a common ancestor dating back over 50 million years. The genomes of all betaherpesviruses vary in the regions flanking a large conserved block of genes spanning UL23 to UL124 in HCMV. There appear to be two distinct evolutionary lineages represented by cytomegaloviruses and roseolaviruses infecting primates (Chapter 14). These lineages are not preserved in lower mammals such as rodents where divergence within the cytomegaloviruses is striking. Similarity between rodent cytomegaloviruses and either primate cytomegaloviruses or roseolaviruses is about the same, and includes the same set of 70 conserved genes. Thus, despite the fact that this subgroup of herpesviruses is the most highly distributed amongst mammals, evolutionary divergence is dramatic. The betaherpesvirus-common genes are composed of 41 herpesvirus core functions discussed in Chapters 3, 4and 14 plus approximately 30 betaherpesvirus-specific gene products that are involved in replication and cell tropism. Biological similarities include tropism for hematopoietic cells in the myeloid lineage (Kondo et al., ; Sissons et al., 2002). In addition to the 70 conserved replication genes human betaherpesviruses HCMV and HHV-6B also have latent genes with a common structure and genomic location (Kondo et al., 1996, 2002b 2003b) suggesting evolutionary conservation in this important process as well. Although little is known about their functions, homologues of several betaherpesvirus-specific genes (UL49, UL79, UL87, UL88, UL91, UL92, and possibly UL95) are common to gammaherpesviruses (see Table 14.1). Thus these two groups are more closely related to each other than to any alphaherpesviruses. Outside of the betaherpesvirus-common genes, there is considerable diversity in this virus group, including the presence of an alphaherpesvirus-like DNA replication origin and origin binding protein in roseolaviruses as well as genes that have been retained only in certain lineages, such as the presence of an adeno-associated virus rep gene homologue in closely related HHV-6A and HHV-6B, but not HHV-7, a gene that is conserved as well in the distant rodent betaherpesvirus, rat cytomegalovirus. The presence of specific immunomodulatory genes in only a subset of cytomegaloviruses is also striking (Mocarski, 2002, 2004). How such an array of distinct gene products entered the betaherpesvirus lineage and why they have been retained remain unresolved questions.