Herpes Simplex Virus
HSV-1 Latency LATs
Category: Virology
from David C. Bloom and Dacia L. Kwiatkowski writing in Alphaherpesviruses: Molecular Virology:
Herpes simplex virus type 1 (HSV-1) latency is characterized by the persistence of viral genomes as episomes in the nuclei of sensory neurons. During this period only one region of the genome is abundantly transcribed: the region encoding the latency-associated transcripts (LATs). The LAT domain is transcriptionally complex, and while the predominant species that accumulates during latency is a 2.0 kb stable intron, other RNA species are transcribed from this region of the genome, including a number of lytic or acute-phase transcripts. In addition, a number of microRNA (miRNA) and non-miRNA small RNAs have recently been mapped to the LAT region of the genome. HSV-1 recombinant viruses with deletions of the LAT promoter exhibit reactivation deficits in a number of animal models, and there is evidence that other LAT deletion mutants also possess altered establishment and virulence properties. The phenotypic complexity associated with this region, as well as evidence that the LATs may play a role in suppressing latent gene expression, suggests that the LAT locus may function as a regulator to modulate the transcription of key lytic and latent genes.
Further reading: Alphaherpesviruses: Molecular Virology
Herpes simplex virus type 1 (HSV-1) latency is characterized by the persistence of viral genomes as episomes in the nuclei of sensory neurons. During this period only one region of the genome is abundantly transcribed: the region encoding the latency-associated transcripts (LATs). The LAT domain is transcriptionally complex, and while the predominant species that accumulates during latency is a 2.0 kb stable intron, other RNA species are transcribed from this region of the genome, including a number of lytic or acute-phase transcripts. In addition, a number of microRNA (miRNA) and non-miRNA small RNAs have recently been mapped to the LAT region of the genome. HSV-1 recombinant viruses with deletions of the LAT promoter exhibit reactivation deficits in a number of animal models, and there is evidence that other LAT deletion mutants also possess altered establishment and virulence properties. The phenotypic complexity associated with this region, as well as evidence that the LATs may play a role in suppressing latent gene expression, suggests that the LAT locus may function as a regulator to modulate the transcription of key lytic and latent genes.
Further reading: Alphaherpesviruses: Molecular Virology
HSV-1 DNA Replication
Category: Virology
from Stacey A. Leisenfelder and Sandra K. Weller writing in Alphaherpesviruses: Molecular Virology:
The cis- and trans-acting elements required for DNA synthesis of Herpes Simplex Virus (HSV) have been identified, and genetic and biochemical analyses have provided important insights into how they work together to replicate the large double-stranded viral genome. Furthermore, viral enzymes involved in DNA replication have provided a rich store of useful targets for antiviral therapy against herpesviruses. Despite these advances, many questions remain unresolved concerning the overall mechanism of genome replication. For instance, it has long been recognized that the products of viral DNA replication are head-to-tail concatemers; however, it is not clear how these concatemers are generated. A recent review summarizes the known functions of viral replication proteins and explore the possibility that these viral proteins may function in combination with cellular proteins to produce concatemers suitable for packaging into preformed viral capsids.
Further reading: Alphaherpesviruses: Molecular Virology
The cis- and trans-acting elements required for DNA synthesis of Herpes Simplex Virus (HSV) have been identified, and genetic and biochemical analyses have provided important insights into how they work together to replicate the large double-stranded viral genome. Furthermore, viral enzymes involved in DNA replication have provided a rich store of useful targets for antiviral therapy against herpesviruses. Despite these advances, many questions remain unresolved concerning the overall mechanism of genome replication. For instance, it has long been recognized that the products of viral DNA replication are head-to-tail concatemers; however, it is not clear how these concatemers are generated. A recent review summarizes the known functions of viral replication proteins and explore the possibility that these viral proteins may function in combination with cellular proteins to produce concatemers suitable for packaging into preformed viral capsids.
Further reading: Alphaherpesviruses: Molecular Virology
Immunity to Herpes Simplex Virus
Category: Virology | Immunology
from Keith R. Jerome writing in Alphaherpesviruses: Molecular Virology:
HSV presents unique challenges to the human immune system. Most of these result from the ability of the virus to establish latency in neurons of the dorsal root ganglia. The first line of defense against the initial establishment of latent infection is the innate immune response. The innate response relies on a variety of cell types recognizing HSV infection via pattern recognition receptors, including toll-like receptors. After exposure, the adaptive immune response is triggered. However, the adaptive response must deal with reactivation of HSV from the latently infected neuron, which in turn seeds mucosal sites with virus. T cells are especially important in this, and likely control both the extent of reactivation from latently infected neurons as well as the extent of viral replication at mucosal sites. Not surprising, HSV has evolved a wide variety of immune evasion mechanisms to tip this balance in its favor and facilitate transmission to new hosts. The study of HSV and its interaction with the host immune system has provided insights into the function of both, and may ultimately facilitate the development of an effective HSV vaccine.
Further reading: Alphaherpesviruses: Molecular Virology
HSV presents unique challenges to the human immune system. Most of these result from the ability of the virus to establish latency in neurons of the dorsal root ganglia. The first line of defense against the initial establishment of latent infection is the innate immune response. The innate response relies on a variety of cell types recognizing HSV infection via pattern recognition receptors, including toll-like receptors. After exposure, the adaptive immune response is triggered. However, the adaptive response must deal with reactivation of HSV from the latently infected neuron, which in turn seeds mucosal sites with virus. T cells are especially important in this, and likely control both the extent of reactivation from latently infected neurons as well as the extent of viral replication at mucosal sites. Not surprising, HSV has evolved a wide variety of immune evasion mechanisms to tip this balance in its favor and facilitate transmission to new hosts. The study of HSV and its interaction with the host immune system has provided insights into the function of both, and may ultimately facilitate the development of an effective HSV vaccine.
Further reading: Alphaherpesviruses: Molecular Virology
Strategies Against Herpes Simplex Virus
from Timothy E. Dudek and David M. Knipe writing in Alphaherpesviruses: Molecular Virology:
Vaccines have been among the most effective public health approaches for protecting individuals against viral disease, with two of the world's most successful vaccines being against smallpox virus and poliovirus. Herpes simplex virus 1 (HSV-1) is a nearly ubiquitous pathogen, and the worldwide prevalence of herpes simplex virus 2 (HSV-2) continues to increase. These two pathogens cause significant morbidity and mortality among the general population, but in particular in neonates and immunocompromised individuals. Perhaps most significantly, there is a 3-4 fold increased risk of HIV acquisition in HSV-2 infected individuals. To date, attempts at producing a vaccine against HSV have not been successful, but each attempt has brought insights into what may be required for an effective vaccine. Furthermore, intense studies into the immunology of HSV infection and the resources that have been put into vaccine design and development have recently yielded knowledge that will be necessary to achieve the goal of a highly effective vaccine against HSV.
Further reading: Alphaherpesviruses: Molecular Virology
Vaccines have been among the most effective public health approaches for protecting individuals against viral disease, with two of the world's most successful vaccines being against smallpox virus and poliovirus. Herpes simplex virus 1 (HSV-1) is a nearly ubiquitous pathogen, and the worldwide prevalence of herpes simplex virus 2 (HSV-2) continues to increase. These two pathogens cause significant morbidity and mortality among the general population, but in particular in neonates and immunocompromised individuals. Perhaps most significantly, there is a 3-4 fold increased risk of HIV acquisition in HSV-2 infected individuals. To date, attempts at producing a vaccine against HSV have not been successful, but each attempt has brought insights into what may be required for an effective vaccine. Furthermore, intense studies into the immunology of HSV infection and the resources that have been put into vaccine design and development have recently yielded knowledge that will be necessary to achieve the goal of a highly effective vaccine against HSV.
Further reading: Alphaherpesviruses: Molecular Virology
Nucleocapsid of Herpes Simplex Virus
Category: Virology
from James F. Conway and Fred L. Homa writing in Alphaherpesviruses: Molecular Virology:
The herpes simplex virion consists of an external membrane envelope, a proteinaceous layer called the tegument, and an icosahedral capsid containing the double-stranded linear DNA genome. The capsid shell is 125 nm in diameter and consists of 162 capsomers (150 hexons, 11 pentons and a portal) which lie on a T=16 icosahedral lattice. The capsid shell consists of four major structural proteins VP5, VP19C, VP23 and VP26 which are the products of the HSV UL19, UL38, UL18 and UL35 genes. In addition to the four major structural proteins the HSV-1 capsid contains a number of minor capsid proteins. These include the UL6, UL15, UL17, UL25, UL28 and UL33 proteins, all of which (along with the HSV-1 UL32 protein) are required for the processing and packaging of replicated viral DNA into preformed capsid shells. The UL6, UL17, UL25 and UL33 proteins remain associated with DNA containing capsids while UL15 and UL28 do not. A recent review summarizes the present knowledge with respect to how the capsid is assembled, how DNA is packaged and what is known about the role of the seven packaging proteins in this process. In addition, recent advances in our understanding the structure of the four distinct types of capsids that are present in HSV infected cells as determined by three dimensional image reconstructions from cryo¬-electron microscopy (cryoEM) are presented and discussed.
Further reading: Alphaherpesviruses: Molecular Virology
The herpes simplex virion consists of an external membrane envelope, a proteinaceous layer called the tegument, and an icosahedral capsid containing the double-stranded linear DNA genome. The capsid shell is 125 nm in diameter and consists of 162 capsomers (150 hexons, 11 pentons and a portal) which lie on a T=16 icosahedral lattice. The capsid shell consists of four major structural proteins VP5, VP19C, VP23 and VP26 which are the products of the HSV UL19, UL38, UL18 and UL35 genes. In addition to the four major structural proteins the HSV-1 capsid contains a number of minor capsid proteins. These include the UL6, UL15, UL17, UL25, UL28 and UL33 proteins, all of which (along with the HSV-1 UL32 protein) are required for the processing and packaging of replicated viral DNA into preformed capsid shells. The UL6, UL17, UL25 and UL33 proteins remain associated with DNA containing capsids while UL15 and UL28 do not. A recent review summarizes the present knowledge with respect to how the capsid is assembled, how DNA is packaged and what is known about the role of the seven packaging proteins in this process. In addition, recent advances in our understanding the structure of the four distinct types of capsids that are present in HSV infected cells as determined by three dimensional image reconstructions from cryo¬-electron microscopy (cryoEM) are presented and discussed.
Further reading: Alphaherpesviruses: Molecular Virology
Herpes Simplex Virus Entry
Category: Virology
from Roselyn J. Eisenberg, Ekaterina E. Heldwein, Gary H. Cohen and Claude Krummenacher writing in Alphaherpesviruses: Molecular Virology:
Membrane fusion allows exchange of materials between cellular compartments enclosed by lipid membranes. Similarly, entry of enveloped viruses into cells allows the viral contents to be delivered by fusion of the envelope with a target cell membrane. Fusion requires disruption of both layers of the two membranes. For most enveloped viruses, a single surface glycoprotein undergoes conformational changes that bring the bilayer of the virus in proximity with that of the host cell and fusion ensues. In contrast, herpesvirus entry requires three virion glycoproteins, gB and a gH/gL heterodimer, that function as the core fusion machinery. Some herpesviruses require additional proteins, e.g. alphaherpesviruses (with a few exceptions) initiate fusion by binding of glycoprotein gD to a cell receptor. A conformational change then exposes the normally hidden receptor binding residues of gD. This change and/or the exposed residues trigger gB and gH/gL to effect virus-cell and cell-cell fusion. Because of the multiplicity of proteins involved in HSV entry as opposed to entry of enveloped RNA viruses, it has been difficult to unravel the mechanism of how the four entry glycoproteins function. Some favor formation of a multiprotein fusion complex while others suggest it may be more of a stepwise process. Solution of the structures of all four entry proteins, coupled with existing and new information has solved much of this mystery. We now have a much better idea of the outline of the process, but the challenge for the future will be to fill in important details. It is clear that entry of HSV occurs in an exquisitely regulated stepwise process that begins with binding of gD to a receptor, activation of the regulatory protein gH/gL which in turn up-regulates the fusogenic activity of gB. Thus, in some ways, HSV entry is remarkably similar overall to entry by simpler RNA viruses, such as influenza. A single fusion protein gB carries out fusion. What distinguishes HSV entry is the double regulation of this process.
Further reading: Alphaherpesviruses: Molecular Virology
Membrane fusion allows exchange of materials between cellular compartments enclosed by lipid membranes. Similarly, entry of enveloped viruses into cells allows the viral contents to be delivered by fusion of the envelope with a target cell membrane. Fusion requires disruption of both layers of the two membranes. For most enveloped viruses, a single surface glycoprotein undergoes conformational changes that bring the bilayer of the virus in proximity with that of the host cell and fusion ensues. In contrast, herpesvirus entry requires three virion glycoproteins, gB and a gH/gL heterodimer, that function as the core fusion machinery. Some herpesviruses require additional proteins, e.g. alphaherpesviruses (with a few exceptions) initiate fusion by binding of glycoprotein gD to a cell receptor. A conformational change then exposes the normally hidden receptor binding residues of gD. This change and/or the exposed residues trigger gB and gH/gL to effect virus-cell and cell-cell fusion. Because of the multiplicity of proteins involved in HSV entry as opposed to entry of enveloped RNA viruses, it has been difficult to unravel the mechanism of how the four entry glycoproteins function. Some favor formation of a multiprotein fusion complex while others suggest it may be more of a stepwise process. Solution of the structures of all four entry proteins, coupled with existing and new information has solved much of this mystery. We now have a much better idea of the outline of the process, but the challenge for the future will be to fill in important details. It is clear that entry of HSV occurs in an exquisitely regulated stepwise process that begins with binding of gD to a receptor, activation of the regulatory protein gH/gL which in turn up-regulates the fusogenic activity of gB. Thus, in some ways, HSV entry is remarkably similar overall to entry by simpler RNA viruses, such as influenza. A single fusion protein gB carries out fusion. What distinguishes HSV entry is the double regulation of this process.
Further reading: Alphaherpesviruses: Molecular Virology