The herpesviruses are extremely successful enveloped DNA viruses. They have been identified in all vertebrate species studied, and extend into other classes of the animal kingdom (oysters, for example). Their replication strategy involves a close adaptation to the immune defense of the host, and it is possible that their evolutionary origins as herpesviruses lie in the origins of immune memory. Eight discrete human herpesviruses are known at this time; each causes a characteristic disease.
Many herpesviruses are neurotropic (i.e., they actively infect nervous tissue); all such viruses are collectively termed alpha-herpesviruses. Three human herpesviruses belong to this group: the closely related herpes simplex virus types 1 and 2 (HSV-1 and -2), which are the primary agents of recurrent facial and genital herpetic lesions, respectively; and varicella-zoster virus (VZV), which is the causative agent of chicken pox and shingles. VZV is more distantly related to HSV. Pseudorabies virus (herpesvirus suis), an important animal pathogen, which has many similarities with HSV is also an alpha-herpesvirus.
Five human herpesviruses are lymphotropic, meaning that they replicate and establish latency in tissues associated with the lymphatic system. These herpesviruses have been subdivided into beta- and gamma-herpesvirus groups based on the specifics of their genome structure and replication. Viruses in these two groups share features that suggest they are more closely related to each other than they are to the three neurotropic herpesviruses.
Infections with human cytomegalovirus (HCMV; the prototype of beta-herpesviruses) are linked both to a form of infectious mononucleosis and to congenital infections of the nervous system. This virus can be devastating in individuals with impaired immune function, such as those suffering from AIDS or being clinically immune suppressed for organ transplantation. The two other lymphotropic herpesviruses — the closely related beta-human herpesviruses-6 and -7 (HHV-6 and HHV-7) — cause roseola, a generally mild early-childhood rash.
Infections with human gamma-herpesviruses, Epstein—Barr virus (EBV) and Kaposi's sarcoma herpesvirus or human herpesvirus-8 (KSHV or HHV-8), are convincingly linked to human cancers. Despite the high frequency of EBV infection in the general population, carci-nogenesis is linked to additional environmental and possibly genetic factors, and the infection in most humans is either asymptomatic or results in a form of mononucleosis that is very similar in course to that caused by HCMV.
Typically, a herpesvirus genome contains between 60 and 200 genes. Unlike adenoviruses, all of which share a basic genomic structure as well as general architecture, a comparative survey of the various herpesviruses' genomic structures displays a staggering array of individual variations on a general theme. Still, within this variation, gene order is generally maintained within large blocks of the genome and varying degrees of genetic homology are clearly evident. The most striking areas of homology are seen among those genes that provide basic replication functions.
One general feature of the complex herpesvirus genome arrangement is that herpes genomes contain significant regions of inverted repeat sequences. The size of herpesvirus genomes varies from 80 kbp to 240 kbp. Given that all the viruses share basic features of productive infection, this range in size means that different herpesviruses differ greatly in the number of "dispensable" genes they encode that are devoted to specific aspects of the pathogenesis and spread of the virus in question. Examples of such differences are described later in this chapter.
Common features of herpesvirus replication in the host
The replication strategies of all herpesviruses appear to share some basic features. The viruses establish a primary infection during which virus replicates to moderate or high titers, yet with generally mild symptoms that are fairly rapidly resolved. One outcome of this primary infection in the host is efficient and effective immunity against reinfection. Following initial infection, however, virus is not completely cleared from the host. Instead, one or another specific cells infected by the virus are able to maintain the viral genomes without a productive virus infection. This maintenance is at least partially a result of the virus' being dependent upon specific cellular transcriptional machinery for high-efficiency replication. The presence of critical components of this machinery is highly dependent upon the state of differentiation and the intercellular environment of cells in those tissues in which the virus replicates and establishes latency. As with other DNA viruses that exhibit a similar pattern of persistence without apparent active infection, this is termed a latent infection. While definitions of latency vary with the virus in question, the strictest definition (which can be readily applied to herpesvirus latency) requires that no infectious virus be detectable in the host during the latent phase.
With appropriate stress to those cells harboring virus along with stress to the host's immune system, the activity of critical components of the cell's transcriptional machinery is activated, and virus can reactivate from latently infected tissue. Provided host immunity is sufficiently suppressed, a generally milder version of the primary infection ensues. This reactivation results in virus being available for infection of immunologically naive hosts, and establishes the infected individual as a reservoir of infection for life. Notably, most of these reactivation events result in the release of virus at the primary site of infection with little or no clinical symptoms! This attests to the stable balance between host and virus that has evolved.
Since the major groups of herpesviruses have evolved to utilize different terminally differentiated cell types as a reservoir in which virus replication must occur at some low level to initiate recrudescence, it follows that those viral genes devoted to the ability of the virus to replicate in the immune competent host will show much divergence. At the same time, the basic similarity of the productive replication cycle, once it occurs, suggests that — as is the case — those viral genes involved in high titer replication will be recognizably similar.
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