Frank J. Jenkins¹ and Sharon L. Turner²

¹ Department of Pathology, School of Medicine; 1Department of Infectious Diseases and Microbiology, School of Public Health;
^1,2 Division of Behavioral Medicine and Oncology, University of Pittsburgh Cancer Institute;
^1,2 Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA 15213 USA

Received 08/02/96; Accepted 08/08/96; On-line 09/01/96

2. INTRODUCTION

In order to understand the different roles of HSV in neuroscience, it is necessary to have a general understanding of the different types of viral infections and the replicative cycle.

2.1. HSV Infections

Infection with HSV can result in several diseases ranging from inapparent infections and self-limiting cutaneous lesions to fatal encephalitis (for a review, see 1). In a primary infection, HSV enters the body via mucosal membrane or abraded skin and establishes a local infection in epithelial cells. Viral replication in these cells results in the amplification of virus, the formation of a 'fever blister', and the activation of both cellular and humoral immune responses. During this acute infection, the virus is transported by retrograde axonal transport to the nuclei of the sensory neurons innervating the site of the local infection (2). Studies using animal models have indicated that a limited viral replication occurs within these neurons followed by the establishment of latency.

A latent infection is characterized by the presence of viral genomes (in the nuclei of sensory neurons) and the absence of viral replication or viral protein production (for review, see 3). The infection and establishment of latency within neurons explain why HSV is termed a neurotrophic virus. In a latently-infected neuron, virus-specific proteins are not produced and, as a result, the host's immune system is unaware of the virus' presence and does not target the latently-infected neuron for destruction. Latent infections ensure the survival and persistence of the virus in the human population.

A latent HSV infection is maintained for the life of the host, but the virus can be reactivated periodically to produce infectious virus and recurrent disease. During reactivation, the viral genome in the latently-infected cell is activated resulting in viral replication. The reactivated virus then travels down the sensory axon where it establishes an infection in the epithelia of the skin. Studies using both animal models and human subjects have shown that viral reactivation can be triggered by a variety of stressful or stress-related stimuli including heat, U.V. light, fever, hormonal changes, menses and physical trauma to the neuron (e.g. 4-7). While the virus appears to be latent most of the time, HSV infection is probably best characterized by recurrent reactivations and periods of latency.

2.2. HSV Replicative Cycle

HSV is a large, enveloped virus that contains an icosahedral nucleocapsid and a amorphous structure termed the tegument located between the nucleocapsid and envelope. For the purposes of this review, we will briefly review the general replication scheme of HSV (depicted in Figure 1). For a detailed review, the reader is directed to Roizman and Sears (8). The enveloped virus particle binds to the outside of a susceptible cell resulting in a fusion between the viral envelope and cellular membrane. As a result of membrane fusion, the nucleocapsid enters the cell cytoplasm and migrates to the nuclear membrane. The viral genome is released from the capsid structure and enters the nucleus through nuclear pores. Once inside the nucleus, viral-specific transcription, translation, and replication of the DNA genome occur. The newly synthesized viral DNA is packaged into preformed capsid structures and the nucleocapsid buds through the nuclear membrane, obtaining its envelope. The replication of HSV is fairly quick, occurring within 15 hours post-infection and is extremely lethal to the cell resulting in cell lysis.

Figure 1. Schematic Representation of an HSV Lytic Replication Cycle.

The genome of HSV is a linear, double-stranded DNA molecule approximately 152 KB in length that encodes for a minimum of 75 separate proteins (9). HSV genes are divided into three temporal classes (alpha, ß, and gamma) which are regulated in a coordinated, cascade fashion (for review see 8). The alpha or immediate-early (IE) genes contain the major transcriptional regulatory proteins and their production is required for the transcription of the ß and gamma gene classes. Of the 5 immediate early genes identified, ICP4 represents the major regulatory protein of HSV. The synthesis of ICP4 is absolutely required for viral replication and this protein is involved in the transactivation of both ß and gamma genes. The ß proteins consist primarily of proteins involved in viral nucleic acid metabolism and are not produced in the absence of alpha proteins. The synthesis of the ß proteins precedes and is required for replication of the viral DNA genome. The gamma proteins consist primarily of virus structural proteins and their synthesis occurs after the onset of viral DNA replication. Molecular studies on a majority of the genes encoded by the HSV genome have demonstrated that many of them can be deleted without interfering with the virus' ability to replicate in cell culture lines (10). In addition, it is possible to construct site-specific mutations, including the deletion of viral genes and the insertion of foreign genes, into the viral genome (11, 12).

The properties of HSV that make it a useful tool for studies in the field of neuroscience include its neurotropism, the ability to construct viral mutants and its ability to establish latent infections in neuronal cells. In this review we will briefly describe several roles for HSV in neuroscience including 1) a model for demyelinating disease, 2) a tool for transneuronal tracing studies, and 3) use as a viral vector for gene therapy.