Herpes simplex viruses (HSV-1, HSV-2; Herpesvirus hominis) produce a variety of infections involving mucocutaneous surfaces, the central nervous system (CNS), and—on occasion—visceral organs. Prompt recognition and treatment reduce the morbidity and mortality rates associated with HSV infections.
The genome of HSV is a linear, double-strand DNA molecule (molecular weight, ∼100 × 106) that encodes >90 transcription units with 84 identified proteins. The genomic structures of the two HSV subtypes are similar. The overall genomic sequence homology between HSV-1 and HSV-2 is ∼50%, while the proteome homology is >80%. The homologous sequences are distributed over the entire genome map, and most of the polypeptides specified by one viral type are antigenically related to polypeptides of the other viral type. Many type-specific regions unique to HSV-1 and HSV-2 proteins do exist, however, and a number of them appear to be important in host immunity. These type-specific regions have been used to develop serologic assays that distinguish between the two viral subtypes. Either restriction endonuclease analysis or sequencing of viral DNA can be used to distinguish between the two subtypes and among strains of each subtype. The variability of nucleotide sequences from clinical strains of HSV-1 and HSV-2 is such that HSV isolates obtained from two individuals can be differentiated by restriction enzyme patterns or genomic sequences. Moreover, epidemiologically related sources, such as sexual partners, mother-infant pairs, or persons involved in a common-source outbreak, can be inferred from such patterns.
The viral genome is packaged in a regular icosahedral protein shell (capsid) composed of 162 capsomeres (see Fig. 177-1). The outer covering of the virus is a lipid-containing membrane (envelope) acquired as the DNA-containing capsid buds through the inner nuclear membrane of the host cell. Between the capsid and lipid bilayer of the envelope is the tegument. Viral replication has both nuclear and cytoplasmic phases. Initial attachment to the cell membrane involves interactions of viral glycoproteins C and B with several cellular heparan sulfate–like surface receptors. Subsequently, viral glycoprotein D binds to cellular co-receptors that belong to the tumor necrosis factor receptor family of proteins, the immunoglobulin superfamily (nectin family), or both. The ubiquity of these receptors contributes to the wide host range of herpesviruses. Replication is highly regulated. After fusion and entry, the nucleocapsid enters the cytoplasm and several viral proteins are released from the virion. Some of these viral proteins shut off host protein synthesis (by increasing cellular RNA degradation), while others “turn on” the transcription of early genes of HSV replication. These early gene products, designated α genes, are required for synthesis of the subsequent polypeptide group, the β polypeptides, many of which are regulatory proteins and enzymes required for DNA replication. Most current antiviral drugs interfere with β proteins, such as viral DNA polymerase. The third (γ) class of HSV genes requires viral DNA replication for expression and constitutes most structural proteins specified by the virus.
After viral genome replication and structural protein synthesis, nucleocapsids are assembled in the cell's nucleus. Envelopment occurs as the nucleocapsids bud through the inner nuclear membrane into the perinuclear space. In some cells, viral replication in the nucleus forms two types of inclusion bodies: type A basophilic Feulgen-positive bodies that contain viral DNA and eosinophilic inclusion bodies that are devoid of viral nucleic acid or protein and represent a “scar” of viral infection. Enveloped virions are then transported via the endoplasmic reticulum and the Golgi apparatus to the cell surface.
Viral genomes are maintained by some neuronal cells in a repressed state called latency. Latency, which is associated with transcription of only a limited number of virus-encoded RNAs, accounts for the presence of viral DNA and RNA in neural tissue at times when infectious virus cannot be isolated. Maintenance and growth of neural cells from latently infected ganglia in tissue culture result in production of infectious virions (explantation) and in subsequent permissive infection of susceptible cells (cocultivation). Activation of the viral genome may then occur, resulting in reactivation, the normal pattern of regulated viral gene expression, replication, and release of HSV. The release of virions from the neuron follows a complex process of anterograde transport down the length of neuronal axons. In experimental animals, ultraviolet light, systemic and local immunosuppression, and trauma to the skin or ganglia are associated with reactivation.
To date, three noncoding RNA latency-associated transcripts (LATs) are the only abundant transcripts in the nuclei of latently infected neurons. Deletion mutants of the genomic region that can become latent have been made, and the efficiency of their later reactivation is reduced. In addition, substitution of HSV-1 LATs for HSV-2 LATs induces an HSV-1 reactivation pattern. Thus, LATs appear to maintain—rather than establish—latency. HSV-1 LATs promote the survival of acutely infected neurons, perhaps by inhibiting apoptotic pathways. Highly expressed during latency, LAT-derived micro-RNA appears to silence expression of the key neurovirulence factor infected-cell protein 34.5 (ICP34.5) and to bind in an antisense configuration to ICP0 messenger RNA to prevent expression of this immediate-early protein, which is vital to HSV reactivation. Studies of individual neurons from cadaveric trigeminal ganglionic explants by microdissection and real-time polymerase chain reaction (PCR) revealed that many more neurons (2–11%) harbor HSV than would be predicted by in situ hybridization studies for LAT and that DNA copy number is similar in LAT-positive and LAT-negative neurons. These findings make it less clear what role LATs play in preventing reactivation. At present, the molecular mechanisms of HSV latency are not completely understood; CD8+ T cells have been found in ganglia of experimental animals and humans and appear to influence the process of reactivation, possibly by inducing antiviral factors such as interferon (IFN) γ. Strategies to interrupt or maintain latency in neurons are not available.
Exposure to HSV at mucosal surfaces or abraded skin sites permits entry of ...