HSV-1A review of HSV-1 and other alphaherpesviruses.
HSV-1from from Alphaherpesviruses: Molecular Virology edited by Sandra K. Weller (2011)
HSV-1 (Herpes simplex virus 1 is a member of the herpes virus family, Herpesviridae read more ...
HSV-1 ICP27from Rozanne M. Sandri-Goldin writing in Alphaherpesviruses: Molecular Virology:
Herpes simplex virus 1 (HSV-1) protein ICP27 is a multifunctional regulator that is essential for HSV-1 infection. ICP27 performs a number of different functions during infection that include inhibiting cellular pre-mRNA splicing, stimulating viral early and late gene transcription by recruiting cellular RNA polymerase II to viral replication sites, binding and exporting viral RNA to the cytoplasm and stimulating translation of some HSV-1 transcripts by binding translation initiation factors. ICP27 also recruits Hsc70 to nuclear foci (VICE domains) that are enriched in chaperones and components of the proteasome, and which are believed to be involved in nuclear protein quality control. ICP27 interacts with a number of proteins and it binds RNA. Post-translational modifications have been demonstrated to regulate ICP27's interactions with several proteins. NMR analysis of the N-terminus showed that it is highly flexible, which may be necessary for switching between different protein interactions. Further, ICP27 undergoes a head-to-tail intramolecular association that may also regulate its interactions, especially with proteins that require that both the N- and C-termini of ICP27 be intact for interaction. A recent review covers the different activities of ICP27 and what we know about how these activities are regulated read more ...
Intrinsic Resistance to HSV-1 Infectionfrom Roger D. Everett writing in Alphaherpesviruses: Molecular Virology:
In recent years it has become apparent that, in addition to the acquired and innate defences against virus infection, there is also a third aspect to antiviral defences that operates at the intracellular level. This concept is known as intrinsic resistance, intrinsic antiviral defence or intrinsic immunity. Its key features include constitutively expressed cellular proteins that restrict viral gene expression, and viral regulatory proteins that counteract the actions of the cellular inhibitors. A recent review reviews the cellular proteins and pathways that are thought to be involved in intrinsic resistance to HSV-1 infection, and the mechanisms by which these are inactivated by ICP0, an important viral regulatory protein. The phenotype of ICP0 null mutant HSV-1 is described to give a background to the phenomenon, then the principal properties of ICP0 itself are summarised. The effects of ICP0 on components of cellular nuclear structures known as ND10 or PML nuclear bodies are reviewed, then the possible roles of these proteins in intrinsic resistance are discussed. The relationships between ICP0, intrinsic resistance and the regulation of viral chromatin structure are considered, and finally the parallels between ICP0 and related proteins expressed by other alphaherpesviruses are described. Intrinsic resistance and the manner in which viruses overcome it are important aspects of the biology of virus infection, but we have much to learn before we achieve a complete understanding of the viral and cellular proteins that are involved read more ...
Roles of ICP22 in HSV-1 Replicationfrom Stephen A. Rice writing in Alphaherpesviruses: Molecular Virology:
ICP22 is the least characterized of the five herpes simplex virus type 1 (HSV-1) immediate-early (IE) proteins. However, accumulating evidence indicates that it carries out a number of interesting regulatory activities inside the infected cell. These include the enhancement of viral gene expression, the modification of RNA polymerase II (RNAP II), and the reorganization of host cell molecular chaperones into nuclear inclusion bodies. Recent studies of engineered HSV-1 mutants indicate that certain of ICP22's activities are genetically separable from each other. Thus, similar to several other of the IE proteins, ICP22 appears to be a multifunctional, multi-domain polypeptide. A recent review summarizes the current state of knowledge concerning ICP22 and its varied regulatory roles during the productive HSV-1 infection read more ...
HSV-1 DNA Replicationfrom 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 read more ...
Nuclear Egress and Envelopment of HSVfrom Joel D. Baines writing in Alphaherpesviruses: Molecular Virology:
In a process unique in biology, all herpesviruses obtain their initial virion envelope by budding through the inner nuclear membrane. In the most prominent model of virion egress, the envelope of the perinuclear virion then fuses with the luminal surface of the outer nuclear membrane, releasing the de-enveloped capsid into the cytosol for subsequent budding events. The pUL31/pUL34 protein complex is a major player in the initial budding event, and mediates several relevant functions including disruption of the nuclear lamina, recruitment of other viral proteins to the inner nuclear membrane and perinuclear virion, and budding of the nucleocapsid through the inner nuclear membrane.
Further reading: Alphaherpesviruses: Molecular Virology
HSV-1 and the DNA Damage Responsefrom Matthew D. Weitzman and Sandra K. Weller writing in Alphaherpesviruses: Molecular Virology:
The cellular DNA damage machinery responds to virus infection and the foreign genomes that accumulate in the nuclei of infected cells. Many DNA viruses have been shown to manipulate the cellular DNA damage response pathways in order to create environments conducive to their own replication. Some cellular factors are activated during infection while others are inactivated read more ...
HSV-1 LatencyLATsfrom 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 read more ...
Oncolytic HSV Vectors for Cancer Therapyfrom Samuel Rabkin writing in Alphaherpesviruses: Molecular Virology:
Oncolytic HSV (oHSV) virotherapy is a promising new strategy for cancer therapy, converting a human pathogen into a therapeutic agent. This takes advantage of the biology of HSV, by introducing genetic alterations that limit virus replication and cytotoxicity to transformed cancer cells while making the virus non-permissive in normal cells. HSV encodes a large number of genes that are non-essential for growth in tissue culture cells, but are nevertheless important for growth in post-mitotic cells and for interfering with intrinsic antiviral and innate immune responses. Many of the cellular pathways regulating growth and antiviral responses are disrupted in cancer cells, which means that viral gene products allowing replication in normal cells are not necessary in cancer cells. In considering the development of an infectious agent for human use, safety is a critical consideration. Therefore mutations targeting cancer cells must be combined with mutations in genes that play important roles in vivo; causing pathogenicity, spread through the nervous system and other organs, latency and reactivation, and adaptive immune responses. This review will focus more on the virological aspects of oHSV vectors and less on the cancer cell target, and describe the multiple strategies and genes involved in generating oHSV vectors. However, it is important to bear in mind that the effect of different HSV mutations will be highly dependent upon the physiology of the particular type of cancer cell and tumor, and that each oHSV vector will be more effective in some tumor types, so that it is unlikely that any one oHSV will be optimal for all types of cancer read more ...
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