Herpes Simplex Virus 1 (HSV-1)-Based Vectors - Viral Vector Approaches in Neurobiology and Brain Diseases - page 49

2 A Short Introduction to HSV-1 Biology

HSV-1 is a widespread enveloped neurotropic human pathogen,
infecting 40-80 % of people worldwide, whose lifestyle is based on
a long-term dual interaction with the infected host. After initial
infection and lytic replication at the body periphery, generally at
the epithelial cells of the oral mucosa where it produces a mild
gingivostomatitis (the primary infection), the virus particles enter
the sensory neurons that innervate the epithelia and travel in retro-
grade direction along the axons to reach the nucleus of the neu-
rons in the sensory ganglia. Following delivery into the neuron
nucleus through the nuclear pore complex, the virus genome will
generally remain in a latent state for long periods. Periodic reactiva-
tion from latency usually leads to the return of the virus to epithelial
cells, where it produces secondary lytic infections resulting in mild
illness symptoms such as cold sores (secondary infections or recur-
rences). A short introduction to selected molecular aspects of the
biological cycle of HSV-1 will help understanding how HSV-1-
derived vectors are generated and used. For a more comprehensive
review on the structure and molecular biology of HSV-1, see [ 1 ].

3 The Virus Particle

The mature extracellular HSV-1 particle, which has a diameter of
approximately 220 nm, is made of 4 concentric layers (1) a core
of double-stranded DNA, (2) an icosadeltahedral capsid composed
of 162 capsomers, (3) the tegument, which is a relatively amor-
phous protein layer located between the envelope and the underly-
ing capsid, and (4) the lipid envelope in which are embedded viral
proteins and glycoproteins, responsible for several functions
including recognition of specifi c receptors and receptor-mediated
cellular entry (Fig. 1 ). The architecture of this particle is highly
complex. Recent proteomic analyses of purifi ed extracellular
HSV-1 particles identifi ed more than 40 virus encoded proteins as
constituents of the mature virus particle, including 8 capsid or
capsid-associated polypeptides, 23 tegument proteins, and 13 gly-
coproteins or membrane-associated proteins [ 2 ]. In addition,
many cellular proteins are present in small quantities in the extra-
cellular particle, mainly in the tegument, but it is not yet clear
whether these cellular proteins play specifi c roles in the physiology
or structure of HSV-1 or if they are mere contaminants.

4 The HSV-1 Genome

The 153-kilobase pairs (kbp) linear DNA genome of HSV-1 that is
packaged within the capsid cavity is devoid of histone proteins. This
long molecule is composed of two elements, designated as L (long)