Infection by herpes simplex virus HSV

There are two related subtypes of herpes simplex virus: types 1 (HSV-1) and 2 (HSV-2), now called human herpesviruses 1 and 2 respectively. Both are large, double-stranded DNA viruses (ca. 150 kb)

encoding 70 or more proteins (HSV-1 has now been completely sequenced). The virion has a large icosahedral nucleocapsid core containing the viral genome as a linear double-stranded DNA molecule. This is surrounded by an amorphous protein-filled tegument which is then enclosed in a membrane envelope containing virion glycoproteins.

Infection starts with attachment of the virion to the cell surface. At present, a number of viral glycoproteins and cellular receptors have been implicated: glycoprotein B binds heparan sulfate on the cell surface whilst glycoprotein C binds complement receptor 1 (CR1 or CD35). Also involved are glycoproteins D and H as well as the cell's basic fibroblast growth factor receptor. Once attached, the virion envelope must fuse with the cytoplasmic membrane to release the viral core into the cell. The core is then transported to the nuclear pores where the viral genome is released into the nucleus to undergo replication and expression. Expression of viral genes may be divided into three broad categories: a (immediate early), p (early) and y (late) genes with transcription and translation taking place in the nucleus and cytoplasm respectively. The progeny virion core is assembled in the nucleus and is thought to then bud out through the nuclear membrane to be transported to the endoplasmic reticulum and Golgi apparatus of the cell where it reacquires its envelope as it buds out from the plasma membrane.

This would be the normal lytic virus lifecycle seen in epithelial cells, however HSV can establish latent infections of neurons in the sensory nervous system. The actual mechanism for establishing, maintaining and reactivating latency is not understood although productive replication is not necessary for establishment. During a latent infection the viral genome is maintained as a multicopy circular episome in the nucleus. There is a family of spliced RNAs present called the latency-associated transcripts (LATs). These transcripts are not required for the establishment or maintenance of latency. Virus reactivates from neurons through an unknown stimulus although in vitro the presence of nerve growth factor stops reactivation.

HSV-1 is associated primarily with orolabial infections, whilst HSV-2 is usually associated with genital lesions; however, these sites are not mutually exclusive. Both viruses are transmitted by direct contact from a productively infected to an uninfected individual through skin abrasions or at mucosal surfaces. Vesicular skin lesions or shallow ulcers on mucosal surfaces result due to the lytic infection of epithelial cells by the virus. Large quantities of virus appear between the epidermal and dermal layer in fluid containing cell debris, inflammatory cells and giant cells. Progeny from this surface infection may pass into sensory nerve endings of the dermis and be transported up the nerve axon by retrograde transport to the cell body as a naked nucleocapsid. An acute infection of the peripheral nervous system may result and usually a latent infection is established primarily in the sensory ganglia (see Figure 1A) but latently infected neurons have also been recovered from the central nervous system. There have been reports of latently infected tissues outside the nervous system but these have been difficult to confirm.

Latent infections in sensory ganglia arc reactivated periodically by unknown means (emotional and physical stress, exposure to UV light, hormones and tissue damage have all been implicated) to produce viral progeny which are transported back down axons to the skin at or close to the original site of infection. Here the virus re-establishes a productive lytic infection which may result in asymptomatic virus shedding or a recurrent (recrudescent) lesion as is suffered by many in the population (Figure IB). HSV-1 reactivates preferentially from cervical and trigeminal ganglia whilst HSV-2 reactivates more readily from sacral ganglia. Recurrences are more likely to occur after severe primary infections and their frequency decreases with time. Reactivated infections may well not reseed the original neuron, which survives infection as sensation is not lost from the periphery even after multiple reactivations.

The first problem for the host in defending itself against HSV is the site of infection. The skin and nervous system have been called 'immune privileged' sites and certainly the immune surveillance occurring in these tissues is not as great as in highly vascularized tissues such as the liver. To compound this problem, especially in recrudescent lesions, the virus is restricted to the epidermal layer until a well-established infection results in enough cell death to cause inflammation in the dermal layer. The second problem for the host is that once the virus has established a latent infection, no detectable viral products are expressed and so there is apparently no way for the host's immune system to attack latently infected cells. However, the immune system does have an important part to play in restricting the severity of HSV infection. Primary infections are usually confined to the skin and dorsal root ganglia but in unusual circumstances a disseminated systemic infection with brain damage and fatal consequences may result. This is seen in patients with T cell defects and neonates. Immunosuppression also increases the risk of recurrences whilst in normal hosts secondary infections are of shorter duration than primary infections.

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