Herpesvirus overview

Herpesvirus Family: Herpesviridae

Herpesvirus	Introduction Virion Structure Genome Characteristics Biological Properties Strategies for Success Herpesviridae Subfamilies Research, Vectors, & Bioengineering General References

Introduction
Herpesviridae is the name of a family of enveloped, double-stranded DNA viruses with relatively large complex genomes. They replicate in the nucleus of a wide range of vertebrate hosts, including eight varieties isolated in humans, several each in horses, cattle, mice, pigs, chickens, turtles, lizards, fish, and even in some invertebrates, such as oysters. Human herpesvirus infections are endemic and sexual contact is a significant method of transmission for several including both herpes simplex virus 1 and 2 (HSV-1, HSV-2), also human cytomegalovirus (HHV-5) and likely Karposi's sarcoma herpesvirus (HHV-8). The increasing prevalence of genetial herpes and corresponding rise of neonatal infection and the implication of Epstein-Barr virus (HHV-4) and Karposi's sarcoma herpesvirus as cofactors in human cancers create an urgency for a better understanding of this complex, and highly successful virus family.

Introduction

Herpesviridae is the name of a family of enveloped, double-stranded DNA viruses with relatively large complex genomes. They replicate in the nucleus of a wide range of vertebrate hosts, including eight varieties isolated in humans, several each in horses, cattle, mice, pigs, chickens, turtles, lizards, fish, and even in some invertebrates, such as oysters. Human herpesvirus infections are endemic and sexual contact is a significant method of transmission for several including both herpes simplex virus 1 and 2 (HSV-1, HSV-2), also human cytomegalovirus (HHV-5) and likely Karposi's sarcoma herpesvirus (HHV-8). The increasing prevalence of genetial herpes and corresponding rise of neonatal infection and the implication of Epstein-Barr virus (HHV-4) and Karposi's sarcoma herpesvirus as cofactors in human cancers create an urgency for a better understanding of this complex, and highly successful virus family.

Virion Structure
All herpesvirus virions have four structural elements. Core. The core consists of a single linear molecule of dsDNA in the form of a torus. Capsid. Surrounding the core is an icosahedral capsid with a 100 nm diameter constructed of 162 capsomeres. Tegument. Between the capsid and envelope is an amorphous, sometimes asymmetrical, feature named the tegument. It consists of viral enzymes, some of which are needed to take control of the cell's chemical processes and subvert them to virion production, some of which defend against the host cell's immediate responses, and others for which the function is not yet understood. Envelope. The envelope is the outer layer of the virion and is composed of altered host membrane and a dozen unique viral glycoproteins. They appear in electron micrographs as short spikes embedded in the envelope.

Virion Structure

All herpesvirus virions have four structural elements.

Core. The core consists of a single linear molecule of dsDNA in the form of a torus.
Capsid. Surrounding the core is an icosahedral capsid with a 100 nm diameter constructed of 162 capsomeres.
Tegument. Between the capsid and envelope is an amorphous, sometimes asymmetrical, feature named the tegument. It consists of viral enzymes, some of which are needed to take control of the cell's chemical processes and subvert them to virion production, some of which defend against the host cell's immediate responses, and others for which the function is not yet understood.
Envelope. The envelope is the outer layer of the virion and is composed of altered host membrane and a dozen unique viral glycoproteins. They appear in electron micrographs as short spikes embedded in the envelope.

Genome Characteristics
Herpesvirus genomes range in length from 120 to 230 kbp with base composition from 31% to 75% G+C content and contain 60 to 120 genes. Because replication takes place inside the nucleus, herpesviruses can use both the host's transcription machinery and DNA repair enzymes to support a large genome with complex arrays of genes. Herpesvirus genes, like the genes of their eukaryotic hosts, are not arranged in operons and in most cases have individual promoters. However, unlike eukaryotic genes, very few herpesvirus genes are spliced. The genes are characterized as either essential or dispensable for growth in cell culture. Essential genes regulate transcription and are needed to construct the virion. Dispensable genes for the most part function to enhance the cellular environment for virus production, to defend the virus from the host immune system and to promote cell to cell spread. The large numbers of dispensable genes are in reality required for a productive in vivo infection. It is only in the restricted environment of laboratory cell cultures that they are dispensable. All herpesvirus genomes contain lengthy terminal repeats both direct and inverted. There are six terminal repeat arrangements and understanding how these repeats function in viral success is an interesting part of current research.

Genome Characteristics

Herpesvirus genomes range in length from 120 to 230 kbp with base composition from 31% to 75% G+C content and contain 60 to 120 genes. Because replication takes place inside the nucleus, herpesviruses can use both the host's transcription machinery and DNA repair enzymes to support a large genome with complex arrays of genes. Herpesvirus genes, like the genes of their eukaryotic hosts, are not arranged in operons and in most cases have individual promoters. However, unlike eukaryotic genes, very few herpesvirus genes are spliced.

The genes are characterized as either essential or dispensable for growth in cell culture. Essential genes regulate transcription and are needed to construct the virion. Dispensable genes for the most part function to enhance the cellular environment for virus production, to defend the virus from the host immune system and to promote cell to cell spread. The large numbers of dispensable genes are in reality required for a productive in vivo infection. It is only in the restricted environment of laboratory cell cultures that they are dispensable.

All herpesvirus genomes contain lengthy terminal repeats both direct and inverted. There are six terminal repeat arrangements and understanding how these repeats function in viral success is an interesting part of current research.

Biological Properties
Four biological properties characterize members of the Herpesviridae family. Herpesviruses express a large number of enzymes involved in metabolism of nucleic acid (e.g. thymidine kinase), DNA synthesis (e.g. DNA helicase/primase) and processing of proteins (e.g. protein kinase). The synthesis of viral genomes and assembly of capsids occurs in the nucleus. Productive viral infection is accompanied by inevitable cell destruction. Herpesviruses are able to establish and maintain a latent state in their host and reactivate following cellular stress. Latency involves stable maintanence of the viral genome in the nucleus with limited expression of a small subset of viral genes.

Biological Properties

Four biological properties characterize members of the Herpesviridae family.

Herpesviruses express a large number of enzymes involved in metabolism of nucleic acid (e.g. thymidine kinase), DNA synthesis (e.g. DNA helicase/primase) and processing of proteins (e.g. protein kinase).
The synthesis of viral genomes and assembly of capsids occurs in the nucleus.
Productive viral infection is accompanied by inevitable cell destruction.
Herpesviruses are able to establish and maintain a latent state in their host and reactivate following cellular stress. Latency involves stable maintanence of the viral genome in the nucleus with limited expression of a small subset of viral genes.

Strategies for Success
The success of herpesvirus infections depends upon several strategies. The first is the fast efficient way the virion invades the host cell, turning off host protein synthesis and releasing viral DNA into the nucleus, where replication and virion production start immediately. Another strategy that herpesviruses share is the ability to thwart attacks from the host. Tactics include inhibiting splicing of mRNA, blocking presentation of antigenic peptides on the cell surface and blocking the apoptosis (cell death) induced by viral gene expression. A third important strategy shared by herpesviruses is their ability to hide their bare, circularized genome in the nucleus of lymphoma and central nervous system cells and then return to productive infection months, even years later. These latent herpesvirus infections are often benign, but can be devastating to newborns and immuno-suppressed individuals.

Strategies for Success

The success of herpesvirus infections depends upon several strategies. The first is the fast efficient way the virion invades the host cell, turning off host protein synthesis and releasing viral DNA into the nucleus, where replication and virion production start immediately. Another strategy that herpesviruses share is the ability to thwart attacks from the host. Tactics include inhibiting splicing of mRNA, blocking presentation of antigenic peptides on the cell surface and blocking the apoptosis (cell death) induced by viral gene expression. A third important strategy shared by herpesviruses is their ability to hide their bare, circularized genome in the nucleus of lymphoma and central nervous system cells and then return to productive infection months, even years later. These latent herpesvirus infections are often benign, but can be devastating to newborns and immuno-suppressed individuals.

Herpesviridae Subfamilies
Alphaherpesvirinae. Members of this subfamily are neurotropic (infect nervous system tissue), have a short reproductive cycle (~18 hr.) with efficient cell destruction and variable host range. The human Alphaherpesvirinae with their commom name, scientific name and the disease they cause are:

Herpes simplex virus 1	Human herpesvirus 1	facial, labial and ocular lesions
Herpes simplex virus 2	Human herpesvirus 2	genital lesions
Varicella-zoster virus	Human herpesvirus 3	chickenpox and shingles

Betaherpesvirinae. Members are lymphotropic, have a long reproductive cycle, restricted host range and infected cells become enlarged (cytomegalo). Human Betaherpesvirinae include:

Human cytomegalovirus	Human herpesvirus 5	infectious mononucleosis
(no common names)	Human herpesvirus 6 & 7	mild early childhood roseola

Gammaherpesvirinae. These herpesviruses are also lymphotropic and specific for either T or B lymphocytes. Members of this subfamily isolated in humans are:

Epstein-Barr virus	Human herpesvirus 4	cofactor in human cancers
Karposi's sarcoma herpesvirus	Human herpesvirus 8	cofactor in Karposi's sarcoma which was extremely rare until the advent of AIDS.

Research, Vectors & Bioengineering
Recent research has uncovered the function or multiple functions of many herpesvirus genes, while some elude understanding and remain the focus of intense study. Other areas of current and future research include understanding the mechanisms for establishing, maintaining and reactivating latency, interactions between viral and host proteins and details of the variety of mechanisms involved in gene regulation.
Herpesviruses are potential vectors for application to several problems in human health. HSV-1 is a good candidate because it is possible to replace large segments of the genome with genes of choice. It's affinity for sensory nerves allows it to target gene therapy to the central nervous system, while it's capacity for cell destruction could be a powerful weapon for selective destruction of cancer cells. An HSV-1 vector could be engineered to express antigens that induce immunity against a variety of infectious agents. Designing such vectors will require profound understanding of the herpesvirus genomes.

Research, Vectors & Bioengineering

Recent research has uncovered the function or multiple functions of many herpesvirus genes, while some elude understanding and remain the focus of intense study. Other areas of current and future research include understanding the mechanisms for establishing, maintaining and reactivating latency, interactions between viral and host proteins and details of the variety of mechanisms involved in gene regulation.

Herpesviruses are potential vectors for application to several problems in human health. HSV-1 is a good candidate because it is possible to replace large segments of the genome with genes of choice. It's affinity for sensory nerves allows it to target gene therapy to the central nervous system, while it's capacity for cell destruction could be a powerful weapon for selective destruction of cancer cells. An HSV-1 vector could be engineered to express antigens that induce immunity against a variety of infectious agents. Designing such vectors will require profound understanding of the herpesvirus genomes.

General References
Three recent publications contain both general and comprehensive reviws of the Herpesviridae family:
Sexually Transmitted Diseases, third edition (1999), ed. Holmes et al., pub. McGraw Hill. Peter E. Pertel, Patricia G. Spear, chapt. 20, "Biology of Herpesviruses", Lawrence Corey, Anna wald, chapt. 21, Genital Herpes", W. Lawrence Drew, Michael P. Bates, chapt. 22, "Cytomegalovirus Infection", and Karen S. Slobod, John W. Sixbey, chapt 23, "Epstein-Barr Virus Infection"
Herpesvirus: Genetic variability and recombination, Kenichi Umene, (1998), pub. Touka Shobo.
Fields Virology, third edition (1996), ed. Fields, Knipe, Howley, pub. Lippincott, Williams & Wilkins. Bernard Roizman, chapt. 71, "The Family Herpesviridae: A brief introduction", and Bernard Roizman, Amy E. Spears, chapt. 72, "Herpes Simplex Viruses and Their Replication"
Two interesting web sites:
Edward K. Wagner at University of California, Irvine, http://darwin.bio.uci.edu/~faculty/wagner/ University of Rochester Medical Center, Intro. to Virology, Herpesvirus (HSV-1, EBV, KSHV) http://www.urmc.rochester.edu/smd/mbi/grad2/pdf/

Bernard Roizman
The Marjorie B. Kovler Oncology Laboratries
University of Chicago
910 East 58th Street
Chicago, IL 60637

Nina Thayer
Biosciences Division
Los Alamos National laboratory
Los Alamos, NM 87544

Curator: Bernard Roizman
Annotator: Nina Thayer

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