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laceemarie

An Inquiry into the Molecular Basis of HSV Latency and Reactivation - Annual Review of ... - 3 views

www.annualreviews.org/...annurev-micro-092412-155654

shared by laceemarie on 15 Oct 14 - No Cached
  • Primary HSV infection of the eye results in herpes simplex keratoconjunctivitis with latency established in the trigeminal nerve.
    • laceemarie
      laceemarie on 17 Oct 14
       
      I was wondering why the primary lit paper was doing there tests in corneal cells. I forgot that there is an HSV that infects the eyes.  What exactly happens to the host cell once the virus is derepressed after latency? I'm sure it has said it in one or both of that papers, but I'm confused by the mechanism. The virus doesn't kill the host cell does it? Being that it resides in nerve cells (which is something new to me) and nerve cells don't replicate, killing the nerve seems like a bad idea for them and for us. Does the presence of the active virus (not latent virus) affect the function of the nerve? As in, does the herpes simplex keratoconjunctivitis affect the trigeminal nerve in that the virus interferes with the transmitting of sensory information from the face to the brain?
    • laceemarie
      laceemarie on 17 Oct 14
       
      *Their tests
  • Notably, antibodies to HSV can routinely be detected in the cerebrospinal fluid of otherwise healthy individuals, implying that HSV can establish latency in the central nervous system and cause an adaptive immune response, as noted above by PCR data (24). It is unlikely that antibodies to HSV are passively transported across the intact blood-brain barrier.
    • laceemarie
      laceemarie on 17 Oct 14
       
      If antibodies can be found in the CSF, then HSV can be found in the CSF, right? Does or could HSV use the CSF as as way to travel to other tissues/nerve cellls?
slgoogin8981

HSV carrying WT REST establishes latency but reactivates only if the synthesis of REST ... - 7 views

www.pnas.org/...E498.long

shared by slgoogin8981 on 15 Oct 14 - No Cached
  • R111 recombinant is not reactivation-defective because it is able to reactivate in the presence of inhibitors of protein synthesis in the same manner as the WT parent virus, and (b) because the only significant difference in the WT and R111 viruses is the presence of the REST gene in the latter virus, the data suggest that expression of this gene blocks reactivation and that suppression of protein synthesis, including that of REST, enables reactivation.
    • becky214
      becky214 on 16 Oct 14
       
      I am confused about when REST blocks reactivation and when it enables it. It says the gene blocks reactivation but continues to say it enables it. Does REST only enable reactivation if it plays a role in suppressing protein synthesis?
  • with dexamethasone or dexamethasone and cycloheximide
  • Specifically, a stress response generated by virus entry recruits or activates REST to enable the assembly of the HCLR complex. Stress responses have been postulated to activate REST
    • becky214
      becky214 on 16 Oct 14
       
      I think this is interesting because REST is not usually found in neurons. I'm curious as to how the neuron recruits this gene. Does the virus actually recruit it? Or is it just a cellular response to the stress of viral entry? 
  • ...13 more annotations...
  • HSV takes advantage of the neuronal stress response to enter into a silent, latent state. To assist in the execution of this plan, HSV evolved a DNA sequence that allows itself to be suppressed in neurons and a mechanism to maintain an equilibrium between total suppression and potential to exit from the latent state.
  • translocated from satellite cells
  • The fundamental question is the identity of the mechanism by which a vigorously replicating virus, on entry into the body, is silenced in neurons harboring latent virus.
    • laceemarie
      laceemarie on 17 Oct 14
       
      Just to make sure that I understand this, once the virus enters the body, it quickly replicates and all the new virus particles find a nerve cell to infect and once there, the virus is able to sit in silence, so to speak?
  • Thus, VP16, a virion protein brought into the cells during infection, recruits several cellular proteins, including LSD1, to derepress α gene promoters
    • laceemarie
      laceemarie on 17 Oct 14
       
      VP16, a virion protein and a recruiter - this protein sounds pretty important to me. Is there a way or has there been work done with this protein to not allow the derepression at this checkpoint? Is it possible to keep a virus in latency because of alpha gene promoters not getting derepressed so as to not allow the virus to infect the host? I'm not sure if that's a reasonable antiviral therapy or not.
  • In some neurons, the virus establishes a latent, silent state. In other neurons, the virus replicates, and it is most likely that the virus in these neurons is transmitted and replicates in other ganglionic cells.
    • laceemarie
      laceemarie on 17 Oct 14
       
      Is this a random event or does this have something to do with the environment of the neuron? I would assume that specific, different environments would be ideal for each.
  • Finally, in contrast to the events following entry of virus after retrograde transport from the periphery, the data suggest that reactivation does not trigger a stress response that leads to activation of REST
    • alexridesducati
      alexridesducati on 17 Oct 14
       
      Has anyone been able to pinpoint the exact step in infection that activates REST so that it can be studied? If so, perhaps it is possible to manipulate the effects of that step in order to induce an artificial response to the reactivation of HSV1 from its latency period in order to retrigger the stress response that leads to REST activation.
  • Thus, VP16, a virion protein brought into the cells during infection, recruits several cellular proteins, including LSD1, to derepress α gene promoters. One α gene product, infected cell protein 0 (ICP0), derepresses β and γ1 genes. Ultimately, the onset of viral DNA synthesis enables the expression of very late, or γ2, genes (4).
    • Sean Hogan
      Sean Hogan on 17 Oct 14
       
      Is this why the latent infection occurs in the ganglia of the PNS? The necessary proteins for gene derepression can't be recruited in the CNS or other cells?
  • In contrast, simultaneous expression of all viral genes during reactivation from latency is likely to minimize yield, but the mission of the virus is to assemble enough viruses to reach the portal of egress from the body (e.g., mouth, genitals) rather than to overwhelm the host with infectious virus.
    • Sean Hogan
      Sean Hogan on 17 Oct 14
       
      This might be the coolest statement in the whole paper. The discussion above kind of painted a picture of HSV infecting the PNS only but the reason for it's inability to reach the CNS didn't receive as much attention. I think this statement summed it all up though.HSV doesn't care about high virion yields or whether a productive or latent infection is necessary, it just wants to reach the body portals. The virus is "smart," enough to avoid the CNS and keep it's host alive.
  • Between 5 and 24 h after excision, mRNAs representative of all viral gene kinetic groups increase 100-fold in amount. Viral DNA also increases in amount, indicating that viral proteins are made. At the same time, viral LAT and miRNA concentrations decrease at least 10-fold (34). It is convenient to define the initial phase lasting no more than 5 h as the preactivation phase and the remaining time interval as the activation phase.
    • rmeloche10
      rmeloche10 on 17 Oct 14
       
      I'm having trouble grasping why the massive disparity between viral DNA and viral LAT. Obviously there would be some disparity when reactivation occurs, but wouldn't the production of more DNA contribute to even a small amount of LAT production and not a minimal 10 fold decrease?
  • The same concentration of HDAC inhibitor was ineffective in inducing the reactivation of R111 recombinant virus in ganglionic organ cultures maintained in medium containing anti-NGF antibody.
    • ameliaobert
      ameliaobert on 18 Oct 14
       
      Interesting: That there is an inhibitor for chromatin remodelling (HDAC). Confusing: Is if HDAC can inhibit properly for WT virus, but not for R111 recombinant, that obtains REST. How does REST make the HDAC inhibitor ineffective ia stressed neuron? I understand that REST is what the DNA can be wrapped about and help with latency, so it that why the HDAC cannot inhibit, since REST is already aiding in latency.
    • nleonard11
      nleonard11 on 20 Oct 14
       
      I thought this process of finding out that the HCLR complex activates from stress was very interesting. Using WT viral genomes appears to be a very effective way to test many virus functions.
    • nleonard11
      nleonard11 on 20 Oct 14
       
      I was just wondering why the virus goes into a latent after 30 days? What exactly is it waiting to do and what conditions need to be present for it to become active again.
    • slgoogin8981
      slgoogin8981 on 19 Nov 14
       
      It would be interesting to know the amount that REST is seen in non-neural cells and nerve cells in the absents of HSV-1. I was state earlier that REST is not normally found in never cells.
Casey Finnerty

Questions Rise on Preparations at Hospitals to Deal With Ebola - NYTimes.com - 0 views

www.nytimes.com/...pitals-to-deal-with-ebola.html

ebolavirus

shared by Casey Finnerty on 14 Oct 14 - No Cached
  • “Usually, an individual is not sick for three to five days after the onset of symptoms, which will fool you,” Dr. Ribner said. “You say, ‘Oh, you’re not going to be that sick.’ Then, around Day 5 to 7, they really crash. Their blood pressure goes down, they become stuporous to unresponsive, and they start to have renal and liver failure. This correlates with the enormous viral load, which is just attacking every organ in the body.”
  • A concern for health workers is that as patients grow sicker, the levels of virus in their blood rise and they become more and more contagious. The researchers at Emory tested patients and found high levels of the virus in their body fluids and even on their skin.At the peak of illness, an Ebola patient can have 10 billion viral particles in one-fifth of a teaspoon of blood. That compares with 50,000 to 100,000 particles in an untreated H.I.V. patient, and five million to 20 million in someone with untreated hepatitis C.
  • “That helped us to understand why, if this is only spread by body fluids, why it is more contagious than hepatitis A, B and C, and H.I.V.,” Dr. Ribner said. “It’s just that there’s so much more virus in the fluids they put out.”
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