Herpes Virus Research Laboratory

Background Information about Herpesviruses

The Herpesvirus Family

Taxonomic assignment of viruses to the herpesvirus family is determined by virion morphology and composition. All herpesviruses have a dsDNA genome contained in an icosahedral capsid composed of 162 capsomers. The capsid is surrounded by a membrane envelope. Over 130 herpesviruses have now been described. Each infects a particular species of vertebrate animal for which the herpesvirus is named and for which it is usually quite selective. Humans are hosts for infection by nine herpesviruses, and the nine are listed below. Some herpesviruses produce economically important diseases in domestic animals and a few of these are also listed below.

Herpesviruses that Infect Humans

Herpes Simplex Virus Type 1-cutaneous lesions
Herpes Simplex Virus Type 2-cutaneous lesions
Varicella-Zoster Virus-chicken pox; shingles
Cytomegalovirus-birth defects; blindness
Epstein-Barr Virus-mononucleosis; Burkitt's lymphoma
Human Herpesvirus 6A--no known disease
Human Herpesvirus 6B--roseola infantum
Human Herpesvirus 7
Human Herpesvirus 8-Kaposi's sarcoma

Some Animal Herpesviruses

Pseudorabies virus (pig)-encephalitis
Equine Herpesvirus 1 (horse)-abortion
Marek's Disease Virus (chicken)-lymphoma

Herpesvirus Structure

The Virion

All herpesviruses consist of an icosahedral capsid surrounded by a membrane envelope. The capsid contains the viral dsDNA. Between the capsid and the membrane is a layer of protein called the tegument. The membrane, tegument and capsid can be seen in the electron micrograph of herpes simplex virus type 1 shown. The overall virion diameter is approximately 200 nm.


The Capsid
The HSV-1 capsid is an icosahedral shell 15 nm thick and 125 nm in diameter. It is composed of 162 capsomers (12 pentons and 150 hexons) which can be seen in the capsid reconstruction shown at the left. Representative pentons are shown in orange and hexons in red.The capsomers lie on a T=16 icosahedral lattice. They are connected in groups of three by trivalent structures called triplexes (green) that lie above the capsid floor and connect the capsomers in groups of three. There are a total of 320 triplexes in the capsid. The capsid mass is approximately 200 MDa without the DNA and 300 MDa with DNA.

Capsid Protein Composition

The mature capsid is composed of seven proteins called VP5, VP19C, VP23, VP26, UL25, UL17 and UL6. VP5 (the major capsid protein) is the structural subunit of the capsomers, both the hexons and the pentons. Hexons are hexamers of VP5 while pentons are pentamers. The triplexes are composed of VP19C and VP23. Most, if not all, triplexes are heterotrimers consisting of one copy of VP19C plus two of VP23. VP26 (blue in the figure above) is located at the distal tips of the hexons. UL25 and UL17 are present on the surface of the capsid as a 1:1 heterodimer. Five heterodimers are found surrounding each capsid vertex. 12 copies of the portal protein (UL6) form a ring at the unique vertex where DNA enters and exits the capsid. Some information about the capsid proteins is given in the table below.

Protein Gene Protein MW Copies per Capsid Location in Capsid
VP5 149,075 149,075 955 Capsomers
VP19C UL38 50,260 320 Triplexes
VP23 UL18 34,268 640 Triplexes
VP26 UL35 12,095 900 Hexon tips
UL25 UL25 62,666 60 Five near each penton
UL17 UL17 74,087 60 Five near each penton
Portal UL6 74,087 12 Unique vertex

The DNA Genome

The HSV-1 genome is a single, linear molecule of double stranded DNA 152,261 base pairs in length. It is divided into two segments called long (L) and short (S) as shown in the diagram below. Short regions of repeated sequence occur at the genome ends and between the L and S segments. As DNA is replicated, the L and S segments invert at a high rate creating a total of four genome isomers. The four occur at equal frequencies in most wt HSV-1 populations. A total of 75 genes for known proteins are encoded with 69 of these present in a single copy and three in two copies each. Among the genes encoded are 43 ancestral or core genes present in all alpha-, beta- and gamma-herpesviruses. All 43 are located in UL and most are conserved genes involved in vital virus functions such as entry of the virus into a host cell, DNA replication, capsid assembly, packaging DNA into the capsid and exit of the capsid for the host cell nucleus. The non-core HSV-1 genes include all US genes and highly divergent genes found at the segment ends. Non-core genes encode proteins involved in lineage- or species-specific functions such as transcriptional transactivation, immune evasion and host cell recognition.

Herpes Simplex Virus Replication

HSV-1 replication begins when virus membrane glycoproteins recognize specific receptors on the cell surface. Virus and cell membranes then fuse in a process that requires glycoproteins B, D, H and L. Fusion results in introduction of the capsid into the cytoplasm as shown diagramatically below. The capsid then migrates to the nucleus where it docks at a nuclear pore and releases its DNA into the nucleoplasm. The virus DNA is replicated in the nucleus where progeny capsids are also formed. Progeny DNA molecules are then packaged into complete, but DNA-free, capsids. Filled capsids then bud through the nuclear membrane, acquire tegument and membrane in the cytoplasm, and exit the host cell.

HSV-1 Capsid Assembly

Assembly of the HSV-1 capsid has been studied in HSV-infected cells, in insect cells infected with recombinant baculoviruses encoding HSV-1 capsid proteins, in extracts of insect cells containing HSV-1 proteins, and in a mixture of purified capsid proteins. Assembly of morphologically normal capsids is found to require VP5, the two triplex proteins (VP19C and VP23) and one or both of two scaffolding proteins, pre-VP22a and VP21. In vitro assembly studies have shown that mature capsids are formed by way of partial procapsid and procapsid intermediates as shown schematically below. Partial procapsids are angular wedges or domes in which a region of capsid shell partially surrounds a region of core. The shell contains VP5 and the triplex proteins while the core is composed entirely of scaffolding protein. Regions of shell and core enlarge until the shell closes to create the procapsid, a spherical structure with the same diameter, number of capsomers and icosahedral symmetry (i.e. T=16) as the mature capsid. Shortly after it is formed, the procapsid is transformed structurally into the matue icosahedral capsid. The scaffolding protein exits the capsid during the morphological transformation and is not found in the mature virion. Packaging of DNA into the capsid is thought to begin at approximately the same time as the procapsid matures and the scaffolding protein is lost.

DNA Packaging

Basic information about HSV-1 DNA packaging can be obtained from electron micrographs, such as that shown at the left, of capsids in the process of DNA encapsidation in vivo. DNA (black in the micrograph) is found to be in the process of entering only complete capsids suggesting capsids are pre-formed before packaging begins. Capsids packaging DNA often appear round rather than angular in profile suggesting they are spherical rather than icosahedral in structure. This shape supports the view that packaging begins with procapsids rather than with capsids having the mature, icosahedral structure.

The mechanism of DNA packaging in HSV-1 is expected to resemble that in dsDNA bacteriophage because of similarities in the mechanism of capsid formation and because of the existence in the HSV-1 genome of genes encoding homologs of bacteriophage packaging proteins. The mechanism of bacteriophage DNA packaging is therefore described briefly below.
The starting materials for bacteriophage DNA packaging are: (1) newly replicated phage DNA, a multi-genome concatemer in which individual viral genomes are linked in a head-to-tail fashion; (2) the phage procapsid containing, at one site, a portal ring through which DNA enters the capsid; and (3) the phage-encoded terminase, an enzyme with multiple functions in the packaging process. Packaging begins when the terminasse makes a double strand cut in the concatemer DNA. The terminase-DNA end complex then docks onto the procapsid by way of the portal as shown to the left in steps 1 and 2. The cut creates one end of the progeny virus genome, and cutting may occur at a specific nucleotide sequence (e.g. the cosN in the case of phage lambda). After cutting, DNA begins to enter the procapsid and continues until terminase makes a second cut in the concatemer DNA. The second cut may occur at a second pac site or after a headfull of DNA has been injected. As DNA is entering, the procapsid is transformed into its mature, icosahedral morphology. Once the last DNA end has entered the capsid, the portal is closed and the capsid is stabilized by addition of head completion proteins (gp2 and gp4 in the case of phage T4).


Genetic studies with HSV-1 have identified a total of seven genes specifically required for DNA processing and packaging into capsids. All seven genes, UL6, UL15, UL17, UL25, UL28, UL32, and UL33, are required for HSV-1 growth in cell culture. When cells are infected with HSV-1 strains with a mutagenic lesion in any of the seven genes, DNA replication and capsid assembly occur normally, but no filled capsids are observed. Functions suggested for the seven processing/packaging genes are listed in the table below.

Protein MW
Presumptive Function
Portal protein
Terminase subunit
Vertex stabilization?
Vertex stabilization
Terminase subunit
Terminase subunit

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