There are 2 antigenic types, HSV-1 and HSV-2 which share antigenic cross-reactivity but different neutralization patterns and tend to produce different clinical symptoms. Man is believed to be the natural host for HSV, but the virus is also capable of infecting various animals, including rodents (good animal models). Human infection is virtually universal - most adults are seropositive.
Interaction of glycoprotein(s) with cellular receptors (not known, but probably different receptors on different cell types - a characteristic of the larger, more complex DNA viruses, and probably common cell surface molecules rather than specific proteins) results directly in fusion of the envelope with the cell membrane. Endocytosis is not absolutely required, but may occur (alternative route for penetration). At least nine of the eleven known herpes simplex virus (HSV) glycoproteins have been characterised regarding their role in virus replication:
Fusion deposits the capsid in the cytoplasm, where it migrates to the nucleus.
The core enters via a nuclear pore where the genome is circularized.
How
Do Animal DNA Viruses Get To The Nucleus? Ann.Rev.Microbiol. (1998) 52: 627-686
Transcription of the large, complex genome is sequentially regulated in a cascade
fashion. ~50 mRNAs are produced by host cell RNA polymerase II.
Three distinct classes of mRNAs are made:
| Alpha (a) - immediate early (IE) mRNAs | 5 trans-acting regulators of virus transcription |
| Beta (b) - (delayed) Early mRNAs | Further non-structural regulatory proteins & minor structural proteins |
| Gamma (g) - Late mRNAs | Major structural proteins |
Gene expression is co-ordinately regulated:
The capacity to establish latency is a characteristic feature of all herpesviruses, and involves three separable phases:
Following natural infection, establishment of HSV latency occurs within sensory neurones innervating the site of primary infection. A lack of permissivity of at least a proportion of sensory neurones results in failure of productive cycle gene expression and failure of entry into the lytic cycle. The neurones in which herpes establishes latency reside primarily in the sensory ganglia, although there is evidence for the presence of latent virus also in the central nervous system (CNS). Transcription during HSV latency occurs from a very restricted portion of the viral genome, which maps to the repeats flanking the unique long region of the viral genome, and is driven by a single viral promoter. The activity of this promoter leads to the generation of a number of nuclear RNAs which have been designated latency-associated transcripts (LATs). Two of those, termed major LATs, of 2.0 and 1.5 kb respectively, are highly abundant non-polyadenylated transcripts, which map in antisense direction to part of one of the IE genes, ICP0. The function of LATs is still not fully understood. Some LAT deletion mutants display a slow reactivation phenotype or appear to establish latency with reduced efficiency.
It has recently been shown that the LATs promote neuronal survival in rabbits after HSV infection by inhibiting apoptosis (Perng GC, et al: Science. 2000 287:1500-1503). The researchers suggest three mechanisms by which this anti-apoptosis function could promote reactivation:
Herpesviruses have evolved a variety of strategies to modulate the host immune response to virus infection. Although the poxviruses were the first DNA viruses shown to encode secreted versions of cellular cytokine receptors, a number of examples have no been discovered in various herpesviruses:
| Virus: | Open Reading Frame: | Function: |
|---|---|---|
| Epstein Barr virus | BARF-1 | Secreted CSF binding protein |
| Cytomegalovirus | US28 | 7-TM CC-chemokine receptor (CCR) homologue |
| Human herpesvirus-8 | ORF74 | 7-TM CXC-chemokine receptor (CXCR) homologue |
Viral DNA replication is the target for a number of successful anti-Herpesvirus drugs (e.g. acyclovir, gancyclovir, etc). The pattern of replication is complex, involving at least 3 potential origins of replication, and resulting in the formation of high molecular weight DNA concatemers.
Virus particles (core plus capsid) assemble in the nucleus - genomic concatemers are cleaved and packaged into pre-assembled capsids.
The envelope is acquired from the inner lamella of the nuclear membrane, and particles accumulate in the space within the inner and outer lamellae. How these particles are transported to the cell surface is not clear and may or may not involve the golgi apparatus. Mutations in certain envelope glycoproteins interfere with cytoplasmic transport. Any remaining virus particles are released when the cell lyses (~24h after infection).
HSV infection appears to be a 'wasteful' process, only ~25% of viral DNA/protein produced is incorporated into virions. The rest accumulates in the cell, which eventually dies. This process produces characteristic nuclear inclusion bodies.
HSV-1 is under active development as a vector for gene therapy. The capacity of the LAT promoter to function during latency, which can last a lifetime, indicates that this promoter has potential for a lifelong expression of therapeutic genes.
Is HSV infection associated with Alzheimer's disease?
Alzheimer's disease affects 10% of people
aged over 65 and 20% of those aged over 75. In the UK, this amounts to about 750,000
cases, and 4 million in the USA. A large proportion of elderly people have HSV in
their brains, irrespective of whether they have Alzheimer's disease. A particular
version (allele) the human ApoE4 gene is known to be a risk factor for the development
of Alzheimer's disease, but by no means all those who carry this allele get Alzheimer's.
The same ApoE4 allele is a strong risk factor for cold sores caused by HSV infection.
Could HSV infection and the ApoE4 allele combine to play a role in Alzheimer's disease?
Itzhaki
RF. et al. "Herpes simplex virus 1 in brain & risk of Alzheimer's disease" Lancet
349: 241-244, 1997.
Dobson
CB, Itzhaki RF "Herpes simplex virus type 1 and Alzheimer's disease" Neurobiol Aging
20:457-465, 1999.
A number of different vaccines are under development against HSV, including DNA vaccines.