HSV1 (Herpes Simplex Virus Type-1) is a member of the Herpes group of viruses, the Herpesviridiae, which includes the important human pathogens HSV2, CMV (Cytomegalovirus), Varicella zoster Virus, EBV (Epstein-Barr Virus), HSV6 and 7, and Kaposis associated Herpes virus, HHV8 (Human Herpesvirus-8). Of these, HSV1 has been the most extensively studied. Human is the only natural host to HSV. The virus is spread by contact and the usual site for the implantation is skin or mucous membrane. Following an initial infection in epithelial cells, the virus spreads to neurons of sensory ganglia, where it becomes latent. The virus emerges sporadically from latency, causing recurrent mucocutaneous lesions. Reactivation of the latent genomes upon stress can lead to re-infection of the epithelial tissue by anterograde spread or in immunosuppressed patients to life-threatening diseases by further retrograde spread (Herpes encephalitis). In rare cases, the virus spreads within the CNS (Central Nervous System) to cause life-threatening encephalitis (Ref.1).
Invasion of cells by HSV1 requires binding of the envelope gC (glyco-protein-C) and/or gB to Heparan sulfate receptors, engagement by gD of one of several co-receptors including HveA (Herpes virus entry mediator A, also known as HVEM, Herpes Virus Entry Mediators), fusion of the viral envelope with the cell plasma membrane and delivery of the viral capsid into the cell cytoplasm (Ref.2). The incoming viral capsids are subsequently propelled along microtubules to the nucleus. They are ultimately targeted via Importin-Beta to the nuclear pore where the viral genome is uncoated for viral transcription and replication in the nucleoplasm. During virus assembly and egress, cytosolic capsids are presumably also transported along microtubules by using kinesins. The core enters via a nuclear pore where the genome is circularized. The virus genome is accompanied by the Alpha-TIF (Alpha Transinducing Factor) protein which functions in enhancing immediate early viral transcription. 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. It consists of two unique regions, UL (Unique long) and the US (Unique short) flanked by the repeated regions (Ref.3). Most viral transcripts are not spliced. There are two main phases of transcription--early, which takes place prior to genome replication, and late, which takes place upon replicated genomes in virus replication compartments formed in the infected cell nucleus. Three distinct classes of mRNAs are made: Alpha, Beta, and Gamma which are regulated in a coordinated, cascade fashion. The Alpha or IE (Immediate-early) genes contain the major transcriptional regulatory proteins and their production is required for the transcription of the Beta and Gamma gene classes. Of the 5 IE genes identified, ICP4 represents the major regulatory protein of HSV and the synthesis of ICP4 is absolutely required for viral replication and transactivation of both Beta and Gamma genes. Immediate early transcription takes place at five promoters immediately upon the viral genomes entering the nucleus. Here, virion-associated Alpha-TIF binds to cellular Oct1, which has bound to TAATGARAT sequences in enhancers upstream of the immediate early promoters. This results in efficient assembly of the pre-initiation complex (Sp1, TBC, CTF and CTB) at the TATA box and RNA Pol-II mediated transcription (Ref.5). IE transcripts are transported to the cytoplasm, translated, and the IE proteins migrate back to the nucleus. All further transcription requires the action of these proteins, especially the Alpha4 protein, which is a generalized transcription activator working by binding multiple sites on the genome and then interacting with nearby TATA boxes to facilitate assembly of pre-initiation complexes and activating Beta or early gene expression. The Beta proteins include the enzymes that are required for replication of the viral genome: a DNA polymerase, a single-strand DNA-binding protein, a primosome or helicase-primase, an origin-binding protein, and a set of enzymes involved in DNA repair and in deoxynucleotide metabolism. Homologues of these proteins are found in virtually all Herpes viruses. Viral DNA synthesis begins shortly after the appearance of the Beta proteins and the temporal program of viral gene expression ends with the appearance of the Gamma or late proteins, which constitute the structural proteins of the virus. This late transcription is controlled by promoters that have different functional architectures, but which both have sequence elements downstream of the TATA box important in stabilizing the formation of pre-initiation complexes. Some strict late promoters contain an element DAS (Downstream Activating Sequence) that interacts with one or more cellular factors DBF (DAS Binding Factor) to mediate the efficient formation of late transcription complexes. The linear 153Kb pair genome circularizes shortly after infection of susceptible host cells and then enters a rolling circle mode of DNA replication generating branched concatameric DNA, which is then cleaved and packaged as unit-length molecules (Ref.4). Viral excretion occurs at or close to the original mucocutaneous site of infection with or without the associated clinical signs and symptoms that accompany reactivation. During the HSV life-cycle, the virus undergoes a lytic cycle. Viral transcription and DNA replication occurs in the nucleus; the particle assembles and exits from epithelial cells in the skin causing a primary infection. The virus then can travel to the nucleus of a sensory neuron establishing latency. Periodic reactivation results in transport of the viral particles from the neuron and re-infects the epithelial cells leading to recurrent lesions.
HSV is a major cause of oral conjunctival, respiratory, CNS, genital and generalized disease. HSV infects mucocutaneous surfaces, and then enters the dorsal root ganglia where further viral replication occurs, followed by a period of latency. HSV1 causes gingivostomatitis, conjunctivitis, keratitis, intense pharyngitis, tonsillitis, and occasionally encephalitis in infants and children during primary infections. Ocular, nasal, orolabial, and oropharyngeal lesions occur in both children and adults. Most adults experience HSV1 infection during their lifetime. HSV2 is more frequently associated with painful genital lesions, urethritis, and cervicitis. Herpes viruses have received a great deal of attention due to their widespread and ubiquitous prevalence in the human population and its ability to establish latent infections in neuronal cells. These properties of HSV make it a useful tool for studies in the field of neuroscience (Ref.6).