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  CHAPTER 24 HERPESVIRUSES Herpesviridae: From Greek herpein (creep), referring to spreading of    lesions  VIRION - Enveloped icosahedral capsid (T=16) - Diameter 125 nm - Diameter of enveloped virion 200 nm - Capsid contains six proteins, envelope contains at least ten glycoproteins. - Material between capsid and envelope, called the “tegument”, contains at least 14 viral proteins. GENOME - Linear, double-stranded DNA, 125  – 250 kb - Contains unique regions, inverted repeat elements, and terminal direct repeat sequences. GENES AND PROTEINS - Herpes simplex virus type 1: 90 different transcriptional units. - Transcribed by cellular RNA polymerase II. - Most mRNAs are unspliced. - Most transcriptional units encode only one protein. Genes are expressed in three temporal classes: ã α (immediate early): early gene activation (six genes) ã β (early): DNA replication, late gene activation ã **** (late): virion proteins, regulatory proteins VIRUSES AND HOSTS   Three subfamilies : alpha, beta, and gamma herpesvirus   Human herpesviruses:    Herpes simplex virus    Varicella-zoster virus    Epstein  – Barr virus    Cytomegalovirus Over 100 known herpesviruses from many animal species. DISEASES    Chickenpox, mononucleosis, pneumonia, hepatitis, encephalitis    Recurrent eye, mouth, and genital lesions    Kaposi’s sarcoma, Burkitt’s ly mphoma, nasopharyngeal carcinoma    Life-threatening infections in immune-suppressed individuals    Neonatal infections, birth defects. DISTINCTIVE CHARACTERISTICS 1.   Tegument proteins function in early steps of virus replication: activation of transcription and host shutoff. 2.   Virion formation begins by budding of nucleocapsids through the inner nuclear membrane. 3.   Many viral genes counter host defenses against virus infection. 4.   Most herpesviruses become latent in the body and can be reactivated months or years after primary infection. Herpesviruses are important human pathogens - Best known as the cause of discomfort from recurring “cold sores”, lesions of the  mucosa of the mouth and lips.   - Genital herpes lesions  are a common sexually transmitted disease, and chickenpox  (varicella-zoster virus) is a common childhood disease that can be serious particularly when people are first exposed as adults.   - Under conditions of reduced immune response found in newborns, transplant recipients, and AIDS victims, herpesviruses can cause serious and often fatal disease, including encephalitis , pneumonia, and hepatitis . - Some cancers are associated with infection by the **-herpesviruses Epstein  – Barr virus and Kaposi’s sarcoma virus (human herpesvirus 8)  Most herpesviruses can establish latent infections - Ability to establish latent infections . - After an initial infection, viral DNA is harbored in a latent state in neurons, B or T lymphocytes , or other cell types. Latently infected individuals can remain without symptoms for months or years, or even their entire life. - Reactivation of latent virus can lead to recurrent disease, such as repeated outbreaks of labial or genital herpes , or herpes zoster (“shingles”) , a localized rash that can occur years after the initial chickenpox infection. - People whose immune systems are impaired can suffer reactivation of cytomegalovirus or Kaposi’s sarcoma virus with dire results . - Herpes simplex virus type 1 and Epstein  – Barr virus infect humans via the oral mucosa, they have very different lifestyles and cause distinct diseases. This is mainly due to the cell types that they target for establishment of long-term latency: neurons for herpesvirus type 1 and B lymphocytes for Epstein  – Barr virus. HERPES SIMPLEX VIRUS   Herpes simplex virus genomes contain both unique and repeated sequence elements - Contain a double-stranded linear DNA genome, which is between 120 and 230 kb in length depending on the virus species.  - The a sequence varies from 200 to 500 bp in length in virus isolates, and contains no open reading frames. - It contains signals for packaging viral DNA in capsids, and enhances recombination between genomes. - Most viral genes are present in only one copy per genome; the UL region contains 65 protein coding sequences, and the US region contains 14. Thus herpes simplex viruses contain at least 84 different genes. The icosahedral capsid is enclosed in an envelope along with tegument proteins - The herpes simplex virus genome is wrapped in a bilayered capsid constructed from six proteins, of which the major one, VP5 (150 kDa), makes up the 162 capsomers. - Arranged as 150 hexamers on the faces of a T=16 icosahedron, and 12 pentamers at the vertices. Another capsid protein, VP26, is located at the tips of the capsomers. - Unlike most enveloped viruses, there is a large amorphous mass between the capsid and the envelope, called the tegument , which contains about 14 virus-coded proteins. Entry by fusion is mediated by envelope glycoproteins and may occur at the plasma membrane or in endosomes - Herpes simplex virus initially binds to heparan sulfate proteoglycans at the host cell surface via viral envelope glycoproteins gB and gC. Subsequently, envelope glycoprotein gD binds to at least two alternative receptors: nectin and herpesvirus entry mediator (HVEM) Viral genes are sequentially expressed during the replication cycle - Transcription of herpesvirus genes is carried out in the nucleus by cellular RNA polyme on the time of their expression during the replication cycle. - Transcription of the immediate early takes place during the first several hours after infection. Tegument proteins interact with cellular machinery to activate viral gene expression and to degrade cellular messenger RNAs - A viral tegument protein known as VP16 forms a complex with at least two key cellular proteins, Oct-1rase II. - The bound protein complex acts as trans activator to enhance the transcription of these genes (first set of viral genes expressed in infected cells) Immediate early genes regulate expression of other herpesvirus genes - A major function of the _ genes is to set up a regulatory cascade that leads to properly timed expression of other viral genes. - ICP0 is a promiscuous activator protein, because its expression activates transcription of many genes introduced into cells by either infection or transfection. - The decrease in the rate of synthesis of gene products at 4 hours post infection involves several proteins in addition to the tegument protein Vhs. - Herpesviruses make their own DNA polymerase, which is directed by other viral proteins to begin DNA synthesis at any one of three viral srcins of DNA replication on the herpes simplex virus genome. DNA replication initially proceeds in a bidirectional fashion from a replication srcin - It has so far been impossible to reconstitute srcin-dependent herpesvirus DNA replication in vitro . - Replicating DNA in infected cells is found as high molecular weight, branched head-to-tail multimers called concatemers , suggesting that DNA is made by a rolling circle mechanism , which can produce linear multimers from a circular template. - Herpesvirus initially sets up bidirectional replication on the circular viral DNA, and only later shifts to rolling circle replication. - UL42, a viral protein that is bound to the DNA polymerase, increases the processivity of the polymerase, allowing it to extend growing DNA strands over considerable distances without dissociating. Rolling circle replication subsequently produces multimeric concatemers of viral DNA - Herpes simplex virus encodes other proteins concerned with DNA metabolism. - Thymidine kinase (UL23), ribonucleotide reductase (UL39/UL40), and deoxyuridine triphosphatase (UL50)  are involved in producing nucleoside triphosphates used as building blocks for DNA replication, while uracil N-glycosylase (UL2)  is involved in DNA repair. These genes are essential for virus replication in non-dividing cells.  Viral nucleocapsids are assembled on a scaffold in the nucleus  - An immature capsid lacking DNA is assembled by accumulation of the major capsid protein VP5 and several other proteins around a scaffold.   - VP24 is actually a viral protease that cleaves itself from a precursor protein, producing VP21 as another cleavage product. - Entry of viral DNA into the capsids is carried out by a multimer of UL6 protein located at one vertex of the capsid, and involves several other nonstructural proteins. Envelopment and egress: three possible routes - Most enveloped viruses bud from cytoplasmic membranes or the plasma membrane to form infectious virions. - Herpesvirus nucleocapsids are assembled in the nucleus, and need to exit this compartment and acquire an envelope. - Herpesviruses use the nuclear membrane to form an envelope as a means of escape from the nucleus. They bud through the inner nuclear membrane into the lumen between the inner and outer nuclear membranes, acquiring an envelope and a layer of tegument proteins. Three distinct theories account for the mechanism by which virus particles exit the cell : 1.   Virions retain their envelopes and are transported to the Golgi membranes within vesicles that bud from the outer nuclear membrane. 2.   Virions lose their envelope by fusion with the outer nuclear membrane, releasing nucleocapsids into the cytoplasm. 3.   Nuclear pores become enlarged and the Golgi membranes are fragmented during viral replication. According to this hypothesis, nucleocapsids exit through the enlarged nuclear pores without an envelope.  Many viral genes are involved in blocking host responses to infection - Herpes simplex virus blocks the presentation of antigenic peptides to the immune system. - A fraction of newly synthesized viral proteins are normally degraded to peptides in proteasomes , especially as a consequence of misfolding. - Herpesvirus genes are tightly packed and are transcribed from both DNA strands. -  Anti-apoptosis genes. Programmed cell death, or apoptosis , results from a complex cascade of events in which a cell can self-destruct. Viral replication is one stimulus that can induce apoptosis. - Wild-type herpes simplex virus blocks apoptosis caused by viral gene expression or by exogenous agents such as osmotic shock, thermal shock, and Fas ligand interaction. Herpes simplex virus establishes latent infection in neurons - Latency is a hallmark of all known herpesviruses in their natural hosts. In humans and experimental animal systems, herpes simplex virus replicates in skin or mucosal cells at the portal of entry, producing infectious virus. - Viral DNA enters the nucleus of the neuron, is circularized, and remains dormant; transcription is repressed and there is no DNA replication. EPSTEIN  – BARR VIRUS - Epstein  – Barr virus was discovered in lymphomas in African children - Epstein  – Barr virus is a very successful pathogen, present in over 95% of the adult population.   - Most primary infections occur in childhood, resulting in largely asymptomatic or unrecognized infections.   - Infection in adolescence and adulthood can cause infectious mononucleosis , a disease whose symptoms are caused by proliferation of infected B lymphocytes and their subsequent destruction by activated T lymphocytes.   - In 1957, Burkitt saw a young boy with swelling of both sides of his jaws that proved to be a lymphoma. He eventually embarked on what he called his “long safari”, documenting  the incidence of the lymphoma in sub-Saharan Africa. - In 1967, Werner and Gertrude Henle, working in Philadelphia, discovered that Epstein  – Barr virus is the agent responsible for infectious mononucleosis. Several other diseases, including nasopharyngeal carcinoma and Hodgkin’s  lymphoma , have been linked to infection with Epstein  – Barr virus. Epstein  – Barr virus infects mucosal epithelial cells and B-lymphocytes - The genome of Epstein  – Barr virus is approximately 180 kb in length, similar to that of herpes simplex virus. It contains fi ve unique sequence elements (U1 to U5) interspersed with one major repeated sequence element (IR1) and three smaller internal repeats (IR2 to IR4). - There are three replication srcins; two of these (Ori-lyt)  are used during productive infection and one (Ori-P)  is used during latent infection. - Like herpes simplex virus, Epstein  – Barr virus DNA circularizes upon entering the cell via a terminal repeat (TR) sequence.  - Epstein  – Barr virus replicates transiently in epithelial cells of the oral mucosa, releasing progeny virus into the saliva. Epstein  – Barr virus expresses a limited set of proteins in latently infected B lymphocytes - In humans infected with Epstein  – Barr virus, approximately one to ten memory B lymphocytes per million B lymphocytes in the blood harbor viral DNA. - Cells derived from Burkitt’s lymphomas also show the latency I gene expression pattern. - The released virus can infect the oral epithelium, giving rise to infectious virus that can spread to other individuals via saliva. - Most latently infected individuals continually produce small amounts of virus throughout their lifetime. Epstein  – Barr virus nuclear antigens direct limited replication of the viral genome and activate viral and cellular genes - EBNA-1 binds to multiple sites within oriP and directs replication of the viral genome, which usually replicates only once per cell division during latent infections. - EBNA-1 also acts to segregate the daughter genomes into each of the two progeny cells during cell division, presumably by binding viral DNA to cellular chromosomes. - EBNA-1 binding within oriP also enhances expression of the latency genes. - EBNA-2 and EBNA-LP together are responsible for transcriptional activation of viral LMP genes and a number of cellular genes.  Latent membrane proteins mimic receptors on B lymphocytes - LMP-1 is an integral membrane protein that mimics the cellular protein CD40, which normally responds to the presence of the CD40 ligand (CD40L). - CD40L is typically expressed on activated T lymphocytes and provides a key costimulatory signal for B-lymphocyte maturation when combined with signals through the B-cell receptor (BCR). case it is the B-cell receptor (BCR), which when paired - LMP-2A has been shown to block signaling through the B-cell receptor, perhaps by sequestering Lyn and Syk and therefore preventing their activation; one result is blockage of the activation of Epstein  – Barr virus lytic replication. - LMP-2A also allows activated B lymphocytes to survive (antiapoptosis) by activating the Ras/PI3-Kinase/Akt pathway Small, untranslated viral RNAs expressed during latent infections target host defense mechanisms - The Epstein  – Barr encoded-RNAs (EBERs) are two small, untranslated RNAs that are transcribed by RNA polymerase III and resemble adenovirus VA RNAs. - It may also provide a survival function during latent infection by acting on cellular proteins involved in protein synthesis such as L22 and La, thereby enhancing cell growth and division. - Since EBERs are abundantly expressed in latently infected cells, their presence is useful as a diagnostic tool for the identifi cation of Epstein  – Barr virus-infected cells in human biopsy material. - A number of microRNAs (miRNAs) are expressed during EBV latent infection. These are encoded within regions of the Epstein  – Barr virus genome defi ned by restriction endonuclease fragments BamHI A and H. - BART miRNAs are most robustly expressed in cells derived from nasopharyngeal carcinomas, whereas the BHRF1 miRNAs are not detected in nasopharyngeal cells but are expressed in B lymphocytes. The targets that have been identified for the miRNAs are diverse and include viral genes such as DNA polymerase and LMP-1. - By repressing the expression of these viral or host proteins at appropriate times in the viral life cycle, the virus may gain an advantage in establishing latency and persisting in humans.

Terror Nocturno

Sep 22, 2019

stf

Sep 22, 2019
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