Two forms of nomenclature are employed for herpesviruses: an informal (also known as vernacular or colloquial) nomenclature that often traces to the early days of virology, and a formal nomenclature that is sanctioned by the ICTV. For example, the virus informally known as Epstein-Barr virus (EBV) is formally known as Human herpesvirus 4. Table 59.1 and e-Table 59.2 include formal and informal names for each virus. In the ICTV-endorsed formal nomenclature, herpesvirus names consist of the family, subfamily, or genus of the natural host of the virus, the word “herpesvirus,” and a serial Arabic number (e.g., Cercopithecine herpesvirus 1; Table 59.1). Human herpesviruses are an exception to the host name rule (e.g., Human herpesvirus 7). ICTV-recognized virus species names are italicized, and the first letter of the first word of the name is capitalized.¹²⁴ It has been proposed to rename herpesvirus species according to their subfamily, for example, Human herpesvirus 1 would be renamed as Human alphaherpesvirus 1, but this has not been formally approved.

The host name–serial number nomenclature system was adopted in 1973^106a in an attempt to rectify problems associated with earlier systems in which viruses were named based on their disease associations, discoverer, geographic source, or whatever inspired the discoverer. Some viruses were given multiple names, and some names were applied to multiple viruses. Naming viruses after their associated diseases caused problems because

some viruses do not cause a specific disease, some viruses cause multiple and quite different diseases, and other viruses cause diseases whose etiologies are comprised of multiple agents. The formal nomenclature scheme was not meant to supplant the informal names that have been grandfathered by time and usage. The intent was to create an orderly system in which each virus would be named unambiguously and independently of classification or properties, which at that time were largely unknown. An important, and sometimes misunderstood, extension of this is that the species number is not intended to imply anything about the relationship between a virus and other herpesviruses that infect the same host species (e.g., HHV-7 and HHV-8 are members of different subfamilies) or between similarly numbered viruses that infect different host species (e.g., EHV-2 and BoHV-2 are members of different subfamilies).

This subfamily is defined on the basis of a variable host range, relatively short reproductive cycle, rapid spread in culture, efficient destruction of infected cells, and capacity to establish latent infections primarily—but not exclusively—in sensory ganglia. This subfamily contains the genera Mardivirus (GaHV-2), Iltovirus (GaHV-1), Simplexvirus (HSV-1), and Varicellovirus (VZV). Simplexviruses and Varicelloviruses have mammalian hosts, while Mardiviruses and Iltoviruses have avian hosts. Reptilian herpesviruses belong to the alphaherpesvirus lineage, but do not belong to any of the currently designated genera.⁷⁶

A nonexclusive characteristic of the members of this subfamily is a restricted host range. The reproductive cycle can be long (over 7 days), and the infection progresses slowly in cultured cells. Infected cells frequently become enlarged (cytomegalia), and carrier cultures are readily established. Betaherpesviruses can establish latency in secretory glands, lymphoreticular cells, kidneys, and other tissues. This subfamily contains the genera Cytomegalovirus (HCMV), Muromegalovirus (MCMV), Proboscivirus (ElHV-1), and Roseolovirus (HHV-6).

The host range of the members of this subfamily is restricted to the family or order of the natural host. In vitro all members replicate in lymphoblastoid cells, and some can lytically infect particular types of epithelioid and fibroblastic cells. Viruses in this group are usually specific for either T or B lymphocytes. Latency is ordinarily established in lymphoid tissue. This subfamily currently contains four genera: Lymphocryptovirus (EBV), Macavirus (AlHV-1), Percavirus (EHV-2), and Rhadinovirus (KSHV). Rhadinoviruses are mainly hosted by primates, Macaviruses are related to the ma lignant ca tarrhal fever viruses of ruminants, and the identified Percaviruses are hosted by per issodactyl and ca rnivore species. The lymphocryptoviruses consist of two major lineages that appear to have co-evolved with their hosts: viruses of Old World (humans, chimpanzees) and New World (marmosets) primates.⁴³,⁷⁷

The core of the mature virion contains a single molecule of the viral genome, in the form of nonchromatinized dsDNA that is packed in an orderly manner in the form of a torus.⁴⁰,⁴¹,⁶⁴,⁹³,¹³⁸ In some herpesvirions, the torus appears to be suspended by a proteinaceous spindle consisting of fibrils embedded in the underside of the capsid and passing through the hole of the torus. The precise arrangement of the DNA in the torus is not known, but the DNA is packed tightly, such that the internal volume of the capsid is approximately equal to the cylindrical volume of the genome. Because of the repulsive forces generated by the negatively charged phosphates that make up the backbone of the genome, such compact packing necessitates the abundant presence in the core of the anion spermine.⁴⁵ Packaging of the viral genome into the capsid core requires ATP and results in a pressurized system that appears to be important for injection of virus genomes through the nuclear pore complex into nuclei of newly infected cells.⁶³

The structural features of the capsid—that is, its 100-nm diameter, 161 capsomeres (150 hexons and 11 pentons), portal complex, and capsid triangulation number (T = 16)— are characteristic of all herpesviruses, including the distantly related fish and oyster viruses.⁹,³¹,⁶⁴ Nonenveloped capsids are present in infected cells in three main forms: A-, B-, and C-capsids.⁴⁴ A-capsids have no core structure, B-capsids contain the assembly scaffold but no genome, and C-capsids are DNA-containing species that no longer house the scaffold. The four conserved capsid proteins that comprise the major structural features of the capsid include the major capsid protein (MCP), the monomer and dimer proteins of the triplex (TRI1 and TRI2, respectively), and the small capsomere-interacting protein (SCP; HSV homologs are listed in Table 59.2). MCP is present in six copies per hexon (6 × 150 = 900 copies per capsid) and five per penton (5 × 11 = 55 copies per capsid), for a total of 955 copies per capsid. The triplex proteins interact with α₂β stoichiometry and form complexes that are present at the 320 sites of threefold symmetry. Hexameric capsomeres are 9.5 × 12.5 nm in longitudinal section; a channel of 4 nm in diameter runs from the surface along their long axis.¹³³ Penton channels are generally somewhat narrower and are nearly closed at their midpoint in B-capsids.¹³⁵ The twelfth pentonal position is the portal for transit of genomic
DNA into and out of the capsid; it is composed of 12 copies of the capsid portal protein (PORT). The portal capping protein (PCP) is associated with mature, DNA-containing nucleocapsids. Cryoelectron microscopic image analysis has enabled reconstruction of capsid structures to greater than 10 Å resolution.¹³⁹ Among other things, this has revealed a unique protein fold in the herpesvirus major capsid protein that is shared with the capsid proteins of tailed DNA bacteriophages, in support of a primordial linkage between these viruses.⁷ Beautiful animated representations of herpesvirus capsids and capsid components are available at http://www.eicn.ucla.edu/animations.

The tegument, a term introduced by Roizman and Furlong¹⁰⁹ to describe the proteinaceous structure between the nucleocapsid and the envelope, has no distinctive features in thin sections but may appear to be fibrous on negative staining.⁹⁰,⁹¹,¹³³ The tegument is sometimes distributed asymmetrically, and its thickness may vary, depending on the location of the virion within the infected cell. When the amount is variable, there is more of it in virions accumulating in cytoplasmic vacuoles than in those accumulating in the perinuclear space.⁴⁰ Some evidence suggests that the amount of tegument is more determined by the virus than by the host.⁷¹ Teguments can contain more than 20 different virally encoded proteins, some of which are present at hundreds of copies per virion. Structural polarity across the tegument has been visualized by immunoelectron microscopy,¹²⁰ indicating that it is an ordered structure, an observation supported by cryoelectron microscopic observations of tegument–nucleocapsid interactions.¹²³,¹³⁴ This is further evidenced by tegument proteins that are closely associated with the nucleocapsid (inner tegument) being acquired in the nucleus and by interactions between envelope glycoproteins and tegument proteins at the tegument periphery. Following nuclear egress, subsequent components of the tegument are likely added in a somewhat ordered manner as the virus particle matures during its trek through the cytoplasm.⁸⁰ One purpose of the tegument is to carry into newly infected cells an assortment, or toolbox, of already synthesized proteins that can immediately begin to manage the host environment to meet the needs of the virus, such as by shutting down host protein synthesis, inhibiting infection-triggered cell defenses, and stimulating viral gene expression.

Electron microscopic studies on thin sections have shown that the outer covering of the virion, the envelope, has a typical trilaminar appearance.³⁸ The presence of lipids was demonstrated by analyses of virions⁵ and by the sensitivity of the virions to lipid solvents and detergents.¹¹⁸ Virion envelopes are derived from patches of altered membrane that trace to the organelle where envelopment occurs.³,⁴⁰,⁶⁶,⁹¹ A major constituent of virion envelopes is a collection of virally encoded glycoproteins. The number and relative amounts of viral glycoproteins vary among herpesviruses. HSV specifies at least 11 different virion-associated glycoproteins, and the copy number of individual glycoproteins can exceed 1,000 per virion. The glycoproteins form numerous protrusions on virion envelopes that are more numerous and shorter than those present on the surface of many other enveloped viruses.¹³³