Herpes Simplex VirusA review of Herpes Simplex Virus and other alphaherpesviruses.
Edited by: Sandra K. Weller"a valuable resource and highly recommended" (BMTW); "insightful reading" (Antiviral Therapy) read more ...
This up-to-date and comprehensive volume distills the most important research in this area providing a timely overview of the field.
Herpes Simplex Virusfrom Alphaherpesviruses: Molecular Virology edited by Sandra K. Weller (2011)
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. Consequences of human herpes simplex virus (HSV) infection include the induction of apoptosis and the concomitant synthesis of proteins which act to prevent this process from killing the infected cell. 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 read more ...
Herpes Simplex Virus Regulatory Protein ICP4from Neal A. DeLuca writing in Alphaherpesviruses: Molecular Virology:
ICP4 is expressed from the HSV genome very early in infection. It is a large structurally complex nuclear phosphoprotein that is essential for viral growth largely due to its requirement for the transcriptional activation of most HSV early and late genes. It also acts a repressor of transcription under certain circumstances. The HSV genome is transcribed by RNA polII, and ICP4 interacts with components of the RNA polII transcription machinery to carry out is functions in transcription. The interactions that are important for its functions can be genetically defined implicating a modular composition of the ICP4 protein. ICP4 also plays a specific role in virus growth in sympathetic neurons implicating a specific function in pathogenesis. A recent review describes what is known about ICP4 from many genetic, biological and biochemical studies, from many laboratories read more ...
Translational Control in Herpes Simplex Virus-infected Cellsfrom Ian Mohr writing in Alphaherpesviruses: Molecular Virology:
Like all viruses, alpha-herpesviruses are completely reliant upon the protein synthesis machinery resident in their host cells. In particular, viral mRNAs must effectively compete with cellular mRNAs to engage ribosomes. To ensure high-level production of the polypeptides required for their lytic replication, multiple independent gene products expressed by the model α-herpesvirus HSV-1 effectively seize control of critical host cell translational control pathways. Surprisingly, while host protein synthesis is profoundly suppressed by global changes in mRNA metabolism, the assembly of a multi-subunit, cap-binding translation initiation factor complex required to recruit 40S subunits to mRNA is directly stimulated. This involves both inactivation of a cellular translational repressor by viral functions, and direct interaction between specific viral proteins and select cellular translation initiation factors. In addition to their dependence on cellular components required for mRNA translation, virus-encoded functions must preserve its activity by neutralizing potent host responses capable of incapacitating the translation machinery, one of which senses stress within the endoplasmic reticulum lumen and another of which functions as a host innate defense component by sensing double-stranded RNA, a molecular signature of viral infection. A recent review discusses in detail the many virus-host interactions that are presently known to control translation in cells productively infected with HSV-1 and highlights recent developments in this area read more ...
Herpes Simplex Virus Entryfrom 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 read more ...
Nucleocapsid of Herpes Simplex Virusfrom 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 read more ...
Apoptosis Modulation During Herpes Simplex Virus Replicationfrom Christopher R. Cotter and John A. Blaho writing in Alphaherpesviruses: Molecular Virology:
Consequences of human herpes simplex virus (HSV) infection include the induction of apoptosis and the concomitant synthesis of proteins which act to prevent this process from killing the infected cell. Recent data has clarified our current understanding of the mechanisms of induction and prevention of apoptosis by HSV; which ultimately establishes a delicate balance of pro- and antiapoptotic modulating factors in infected cells. These findings emphasize the fact that modulation of apoptosis by HSV during infection is a multicomponent phenomenon involving a combination of viral and cellular factors read more ...
Vaccines and Antiviral Strategies Against Herpes Simplex Virusfrom 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 read more ...
Immunity to Herpes Simplex Virusfrom 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 read more ...
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