Herpesviruses

Seven herpesviruses have been isolated from humans:

HSV-1	Herpes simplex 1	Fever blister
HSV-2	Herpes simplex 2	Genital/neonatal herpes
CMV	Cytomegalovirus	Interstitial pneumonia
VZV	Varicella-zoster virus	Chicken pox and shingles
EBV	Epstein-Barr virus	Burkitt’s lymphoma, mononucleosis
HHV-6	Human herpesvirus 6	Roseola
HHV-8 / KSHV	Human herpesvirus 8 / Kaposi’s sarcoma herpesvirus	Kaposi’s sarcoma

General structure and classification

double-stranded DNA with an icosahedral core surrounded by a lipoprotein envelope

icosahedral capsid (containing 162 capsomeres)

outer enveloped derived from nuclear membrane of host

DNA ~150-200 Kbp (85-100 genes), characterized by multiple repeat sequences.

Herpesviridae classified into three subfamilies:

a (HSV-1, HSV-2, VZV) – variable host range, rapid replication (in vitro), effective destruction of host cell, latency in neuronal cells

b (CMV) – restricted host range, slow replication (in vitro), infected cells are frequently enlarged (cytomegalia), latency in secretory glands, kidneys, other tissues.

g (EBV, HHV-8) – highly restricted host range, limited growth (in vitro), efficiently infect lymphocytes, frequently enter latency after infection, resulting in the transformation of the cells.

Replicative Cycle

note: though HSV replicative cycle is described, it is similar to most other herpesviruses

Acute Infection: HSV attaches to the cell surface at the site of the receptor for fibroblast growth factor (different receptors in other viruses). After entry into the cell, the virion is uncoated and the genome DNA enters the nucleus and is circularized. Early viral mRNA is transcribed by host cell RNA polymerase and then translated into early, nonstructural proteins in the cytoplasm. Two of these early proteins, thymidine kinase and viral DNA polymerase (see below), are important because they are sufficiently different from the corresponding cellular enzymes to be involved in the action of antiviral drugs, eg, acyclovir.

The viral DNA polymerase replicates the genome DNA, at which time early protein synthesis is shut off and late protein synthesis begins. These late, structural proteins are transported to the nucleus, where virion assembly occurs. The virion obtains its envelope by budding through the nuclear membrane and exits the cell via tubules or vacuoles that communicate with the exterior.

Latent Infection: In latently infected cells, multiple copies of HSV DNA are found in the cytoplasm of infected neurons. Only a few genes are transcribed, and none are translated into protein.

Replication and the temporal transcription

as mentioned above, herpesvirus transcription happens in stages. This happens in almost all DNA viruses.

Early genes: set of defined genes transcribed before the onset of DNA replication.

Late genes: set of defined genes transcribed after the onset of DNA replication.

Complex viruses (like HSV) also have:

a polypeptides: immediate early polypeptides expressed before the onset of protein synthesis

b polypeptides and g polypeptides: delayed early and late polypeptides which require protein synthesis for expression

VHS: are gene products that repress expression of host genes and degrade host RNA.

a = transcriptional regulation, b = necessary for DNA replication, g ₁ and g ₂ = structural genes for virion formation

Molecular events:

(1) Virion component serves as a transcriptional factor to "turn on" the a genes (sequence specific transcriptional factors).

(2) a polypeptides Þ b polypeptides Þ g polypeptides and shut-off a polypeptide expression.

(3) b polypeptides (and maybe a polypeptides too) make viral DNA polymerase, DNA-binding proteins, and thymidine kinase. All are involved in viral DNA replication. Targets for anti-viral drugs (acyclovir for thymidine kinase, phophonoacetate for polymerase).

(4) g polypeptides, made late in life cycle, are mostly viral structural proteins.

Molecular switch of latency

Herpesviruses are noted for their ability to cause latent infections. In these infections, the acute disease is followed by an asymptomatic period during which the virus remains in a quiescent (latent) state. When the patient is exposed to an inciting agent or immunosuppression occurs, reactivation of virus replication and disease can occur.

Switching from acute Þ latent, and latent Þ acute infections is unclear.

It is likely that a factor/factors that facilitate transcription of most other gene products is lost.

Example: in EBV infected B-cells a single viral gene product called Zebra can trigger the cascade of a , b , and g transcriptions. This was demonstrated in B-lymphoma cell lines where all but 4-6 EBV genes are expressed!