Herpes Virus Life Cycle PDF

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These lecture notes give an overview of the Herpes virus, its epidemiology and classification. There is significant focus on the replication cycle of the virus, its latency and association with cancer....

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HERPES VIRUS LIFE CYCLE (L8) Wednesday, January 6, 2021 12:42 PM

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Enveloped viruses. 8 are chemically important, 9 known to infect humans. Cold sores, sexually transmitted. DNA viruses (ds linear) -> surrounded by an icosahedral capsid. Replicates its genome in the nucleus. Assembles itself in the nucleus. All share the same morphology, replication and latency cycle (recurrent infections from that same first infection). Two associated with cancer: HHV-8 (Karposi's sarcoma), EBV (mononucleosis). Increased risk for severe herpes virus: HIV, elderly, young, infants, pregnant, foetus. Has glycoproteins for attachment, fusion, immune evasion (e.g. MHC-I like molecule, pseudo IL-10 which is anti-inflammatory). Acyclovir, gancyclovir, valgancyclovir = can be used to target and treat herpes virus life cycles. Tegument: between the envelope and the capsid. Full of herpes virus proteins which are important for its first entry into the host cell, inactivate innate immune system e.g. producing MHC-I like molecules, production of pseudo IL-10) and assembly of new virions. Receptor mediated entry into cell. Categorised into sub-families: a, β, γ.

HERPES VIRUS LIFE CYCLE: LYTIC AND LATENCY CYCLE:  Lytic cycle: replication of its genome, new virions produced, highly immunogenic (easily detected by the immune system), full range of virus proteins produced  Latency: no virus protein expression, viral DNA maintained as an episome that gets replicated with host DNA, immunologically silent (not detected by the immune system). LYTIC CYCLE: ENTRY:  All the herpesviruses express the same glycoproteins that will help them bind and fuse with the host cell: glycoprotein B (gB), glycoprotein H (gH), glycoprotein L (gL). 1. Herpesvirus can enter the host cell in two ways: a) direct fusion with plasma membrane and capsid with the genome gets released into cytoplasm, b) fusion with endocytic membrane (receptor mediated entry) -> taken up into a vesicle/endosome where viral envelope fuses with the vesicular/endosomeal membrane and capsid with genome released into cytoplasm (endosomal escape). 2. Viral tegument begins the shutdown of antiviral response e.g. PML bodies, interferon signalling, DNA damage response, activation of pro-inflammatory pathways.

3. With the help of active transport the capsid moves along the microtubules, the capsid reaches the nucleus where it will secure itself on the nuclear envelope -> its viral DNA enters the nucleus where it will circularise. 4. Don't require the host machinery to replicate. Instead, they encode their own proteins called the immediate early proteins (a) which allow the viral DNA to replicate. The immediate early genes are expressed with the help of cellular RNA polymerases Pol II. The only host molecules they require are the nucleic acids and energy as the virus also encodes for the enzymes that catalyse these reactions. 5. These proteins will transactivate the expression and transcription of the early proteins (β) which are 5 in total: polymerase, origin binding protein, helicase/primase, ssDNA binding protein, DNA processivity factor. 6. These proteins now allow the viral DNA to replicate properly and it does so in a "rolling circle" mechanism. 7. Following this, the early proteins will upregulate the production of the late proteins (γ). These proteins are what are required to make a new herpes virus so it includes structural proteins (minor capsid protein, major capsid protein), tegument proteins, glycoproteins (gB, gH, gL) etc. It is important to note, that each stage of protein production is reliant on the previous stage (early proteins rely on immediate early, late rely on early proteins for activation). 8. The glycoproteins embed themselves into the host membrane where they will be picked up as the virus moves towards exiting the cell. The viral structures assemble, the DNA does not remain circular anymore if it is going to be used for a new virus, the capsid forms around the DNA and the virus will exit the nucleus through a process called nuclear egress (picks up an envelope as it moves from the nucleus to the perinuclear space but it loses it again when entering the cytoplasm). 9. The tegument assembles and the virus picks up its second envelope (2o envelopment) from the Golgi apparatus. 10. New virus moves towards the plasma membrane of the host cell where it picks up its glycoproteins (takes part of the host membrane too) and it is now released as a new infectious virus. DISEASE ASSOCIATIONS (HERPES SIMPLEX VIRUS-HSV): Infection via mucosal surfaces (oral, genital) -> invade sensory nerve endings. CLINICAL SIGNS AND SYMPTOMS FOR HSV-1:  Encephalitis.  Conjuctivitis.  Oropharyngeal herpes (virus in the nerve endings of the mouth).  Primary genital herpes as well as recurrent.  Herpes whitlow (fingers).  Mucocutaneous disease in the immunocompromised. -HSV-1 can invade the sensory nerves of the face (trigeminal nerve). It can move into the trigeminal ganglion where it inactivates (remains latent). Upon reactivation the virus can move back down the nerve fibres and cause the same initial infection it did the first time round. However, it can also travel up the ganglion and reach into the brain where it can

cause serious inflammation (encephalitis). It is not known what causes the virus to reactivate but UV is thought to be one. CLINICAL SIGNS AND SYMPTOMS OF HSV-2:  Meningitis.  Oropharyngeal herpes.  Perianal herpes.  Primary genital herpes as well as recurrent.  Herpes whitlow. -HSV-2 invades, replicates and remains latent in the sacral ganglia. -HSV-2 also known as herpes genitalis. -Prevalence is 5-10% amongst 20-40 year olds. -Usually asymptomatic reactivation and much more frequent than HSV-1. -Easy to transmit, harder to manage. Vaccines in clinical trials to improve the immunological response and rate of reactivation. HERPES SIMPLEX AND IMMUNOCOMPROMISED AND NEONATES:  Presentation of symptoms in the immunocompromised are much more severe.  This could be due to being post-transplant so the severity of it is directly related to the type of immunotherapy they are on.  Can develop pneumonitis, oesophagitis, gastritis as it can spread much easier to these areas.  In people with AIDS, the symptoms are much more exaggerated, reactivation is much more frequent as well as more resistant to antivirals.

CYTOMEGALOVIRUS (CMV):  Transmission: bodily fluids, breast milk, sexual, urine, blood products, organ donation, bone marrow.  A type of herpes virus.  Infection usually asymptomatic.  Around 8% are symptomatic and would present with fever, mononucleosis, hepatitis.  Can be congenital (infected mother has a 40% chance of passing it on) -> microcephaly, petachiae, jaundice, HSM, neurological abormalities.  In immunocompromised, frequent monitoring for CMV re-activation is required: transplant-solid, haematopoietic stem cell -> pneumonitis, oesophagitis, gastritis, enterocolitis, hepatitis, retinitis, graft-host disease -> HIV/AIDS: retinitis, gastritis, enterocolitis, pneumonitis, hepatitis. VARICELLA-ZOSTER VIRUS (CHICKEN POX):  Primary infection = chicken pox.  Reactivation = shingles.  Transmission: contact, droplet infection (saliva).  Latency in spinal ganglia and satellite cells.  Active immune function supresses reactivation.

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Reactivation seen in: immunosuppressed, elderly where immune system not as efficient as it used to be. Virus transported to skin via sensory nerve endings where it replicates -> shingles.

EPSTEIN-BARR VIRUS (EBV):  Transmission: saliva (kissing).  Primary infection: usually asymptomatic, 4-7 week incubation period.  Replication in oropharyngeal epithelial cells and B-cells.  Usually happens during childhood.  Symptomatic primary infection: infectious mononucleosis (glandular fever), fever, pharyngitis, swollen lymph nodes, hepatitis.  Malignancies are associated with EBV: B-cell malignancies (Burkitt lymphoma, Hodgkin lymphoma), epithelial malignancies (nasopharyngeal carcinoma-100%, gastric carcinoma-10%), T-cell and NK-cell malignancies (Extranodal NK/T cell lymphoma, NK leukaemia).  EBV associated malignancies in immunocompromised: 1. Post transplant malignancies -> Hodgkin lymphoma, lymphoproliferative disease. 2. Post transplant diseases: encephalitis/myelitis, pneumonia, hepatitis. 3. EBV and HIV related lymphomas: Burkitt lymphoma, diffuse large B-cell lymphoma, primary CNS lymphoma, Hodgkin lymphoma, plasmablastic lymphoma, primary effusion lymphoma.  Latency in B-cells.

HUMAN HERPES VIRUS 6 & 7:  Oral infections in childhood (HHV6 > 90%, HHV7 > 60%).  Transmission: droplets, saliva.  Symptoms: fever, swollen lymph nodes, rash, rarely meningitis.

HUMAN HERPES VIRUS 8 (HHV8-KAPOSI'S SARCOMA ASSOCIATED HERPES VIRUS-KSHV):  Cancer causing herpes virus.  Latency in B-cells and endothelial cells.  Herpes virus detected in the sarcoma (genome sequenced).  Kaposi's sarcoma -> endothelial cells.  Primary effusion lymphoma (PEL) -> B-cells.  Multicentric Castleman's disease (MCD) -> B-cells.

HERPES VIRUS LATENCY:  Characterised by 3 general properties: cells containing the latent genome are poorly detected by the immune cells, viral gene products seen in active infection not detected, the viral genome persists intact so that infection can be initiated.  Latency in neurones (HSV-1, HSV-2, VZV).  Some of the viruses tether their DNA to the chromosomal DNA such that it replicates each time alongside the host DNA (EBV-EBNA 1, KSHV-LANA).

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Latency in stem cells: HSCs (CMV) -> reactivate during proliferation or inflammation. As the stem cell differentiates and proliferates, CMV also replicates -> highly expressed in macrophages, low expression levels in DCs....