Herpesviruses

100 nm

Herpesvirus structures are unique, with tegument layer present and genomic DNA wrapped around core

Herpesviridae• Large family of large, complex viruses• Infect vertebrate hosts• Three subfamilies:

– Alphaherpesvirinae, 2 genera– Betaherpesvirinae, 3 genera– Gammaherpesvirinae, 2 genera

• Very important as human pathogens• Cause cold sores, genital herpes, chicken pox, shingles,

mononucleosis and many other diseases• Infection is for life – herpesviruses become latent in hosts, then

reactivate

Nucleocapsid contains core of protein wrapped in genomic DNA

Cryo-EM shows regular, external structure preserved

Irregular structures often seen in micrographs are artifacts of distortion from negative staining

Herpesvirus particles • Genome: Single large segment of dsDNA, ~ 3% of particle

weight (124-235 kbp)• Core: Nucleic acid wrapped around cylindrical structure 25-30

nm• Capsid: T=16 icosahedron composed of 162 capsomeres (150

hexamers and 12 pentamers), capsid diameter 100-110 • Tegument: poorly defined material between capsid and

envelope, contains alpha trans-inducing factor (α-TIP) necessary for activation of α genes and virion host shutoff protein (VHS)

• Envelope: Derived from nuclear membrane, surrounds tegument, has spike glycoproteins – virion diameter 120-200 nm

Major Herpesvirus structural proteins

Herpesviruses• HHV1, Herpes simplex 1

– Cold sores, epithelial and neuronal cells

• HHV2, Herpes simplex 2– Sexually transmitted disease (STD), also as above, teratogenic, can be fatal in

newborns

• HHV3, Varicella-zoster– Chicken pox, shingles

• HHV4, Epstein Barr virus– Mononucleosis, Burkitt’s lymphoma, lymphoid tissue only

• HHV5, Cytomegalovirus– Salivary gland tropic, teratogenic, can be fatal in newborns

• HHV6, Roseolovirus– Childhood rash, multiple sclerosis?

• HHV8– Associated with Kaposi’s sarcoma HSV 6,7,8 all identified

after 1990, after HIV

Biology of herpesviruses• All specify a large array of enzymes involved in

nucleic acid metabolism• Virus DNA synthesis and capsid assembly in

nucleus• Production of infectious progeny is

accompanied by destruction of infected cell• A single virus can cause several diseases• Herpesviruses remain latent in the host for life,

and can be reactivated to cause lesions at or near the initial infection site

HHV genomes

Vary in size, structure, positions of repeats

HHV 1 genome occurs as approximately equal quantities of four isomers

Short and long regions of viral genome are inverted relative to each otherOther herpesviruses may have 1, 2, or 4 isomeric DNA forms

Two models for DNA replication of herpesvirus; details are still poorly understood

- DNA nicked- DNA replication is discontinuous- RNA primed- by rolling circle mechanism?

Recent studies on HHV1 replication do not support a rolling circle model, but rather a complex set of concatameric intermediates

Human Herpesvirus 1 particles and genome organization

1-4.Membrane fusion, release of tegument and VHS.

5-8. Nucleocapsids transported on microtubules to nuclear membrane, ejects DNA which circularizes.

9-10. Transcription, export, translation of immediate early genes by cellular Pol II

11-13. Transcription, translation of early genes; genome replication in nucleus.

14-18. Transcription, translation of late (structural) protein genes; import to nucleus, nucleocapsid assembled and stuffed with DNA.

19-23. Nucleocapsid/tegument buds into ER lumen; acquires envelope, egress by fusion.

Herpesvirus infection cycle

Herpesvirus packaging

• Phage-like process• Empty particle with single

portal assembled first• Genomic DNA stuffed

through portal• pac1 and pac2 signals on

genomic DNA are required for insertion of DNA through portal and cleavage of unit length DNA once headful is achieved

Herpesvirus latency

Occurs in neurons, steps 1-7 probably like productive infection; normal viral transcription blocked (leaky), latency-associated RNAs transcribed, spliced,

2kb LAT in the form of lariat transported to cytoplasm, translated to LAT proteins

LAT genes are clustered; micro RNAs regulate LAT mRNA expression

Phylogenetic relationships among orthopoxviruses

Closest relatives of herpesviruses are phycodnaviruses, viruses the infect algae

Relationships among large dsDNA viruses

Closest relatives of poxviruses are baculoviruses, viruses the infect insects