John SinclairCorresponding Author Contact Information, a, E-mail The Corresponding Author aDepartment of Medicine, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK
Received 21 September 2007; revised 7 November 2007; accepted 9 November 2007. Available online 15 February 2008.
Abstract
Human cytomegalovirus (HCMV) persists as a sub-clinical, lifelong infection in the human host which is maintained at least in part by its carriage in the absence of detectable infectious virus: a hallmark of latent infection.
In contrast, reactivation from latency in immuno-compromised individuals can result in serious disease.
Understanding virus latency and reactivation, therefore, is essential for a full understanding of the biology and pathogenesis of this persistent human herpesvirus.
However, the precise cellular sites in which HCMV is carried and the mechanisms regulating its latency and reactivation, during natural infection, remain poorly understood.
Recent work, however, has led to a consensus opinion that cells of the myeloid lineage are one site of carriage of HCMV in vivo and that in myeloid dendritic cell (DC) progenitors the viral genome is carried latently in the absence of virus lytic gene expression.
In contrast, differentiation of these cells to a mature DC phenotype is linked with reactivation of infectious virus resulting from differentiation-dependent chromatin remodelling of the viral major immediate-early promoter.
Thus there is a crucial link between the differentiation of myeloid cells and transcriptional reactivation of latent virus which is likely to play a key role in viral pathogenesis.
Keywords: Human cytomegalovirus; Latency; Reactivation; Dendritic cell; Bone marrow progenitor; Latency-associated transcripts
Journal of Clinical Virology Volume 41, Issue 3, March 2008, Pages 180-185 CMV Special Issue, 11th International CMV and Beta Herpesvirus Workshop
-------------------- Note: I'm NOT a medical professional. The information I share is from my own personal research and experience. Please do not construe anything I share as medical advice, which should only be obtained from a licensed medical practitioner. Posts: 4881 | From Middlesex County, NJ | Registered: Jul 2006
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AliG
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Gavin W.G. Wilkinsona, Corresponding Author Contact Information, E-mail The Corresponding Author, Peter Tomaseca, Richard J. Stantona, Melanie Armstronga, Virginie Prod'hommea, Rebecca Aichelera, Brian P. McSharrya, Carole R. Rickardsa, Daniel Cochranea, Sian Llewellyn-Laceyb, Eddie C.Y. Wangb, Cora A. Griffina, 1 and Andrew J. Davisonc aDepartment of Medical Microbiology, Cardiff University, Tenovus Building, Heath Park, Cardiff CF14 4XX, UK bDepartment of Medical Biochemistry, Cardiff University, Tenovus Building, Heath Park, Cardiff CF14 4XX, UK cMRC Virology Unit, Institute of Virology, Church Street, Glasgow G11 5JR, UK Received 12 September 2007; accepted 11 October 2007. Available online 15 February 2008.
Abstract
Human cytomegalovirus (HCMV) causes lifelong, persistent infections and its survival is under intense, continuous selective pressure from the immunenext term system.
A key aspect of HCMV's capacity for survival lies in immune avoidance. In this context, cells undergoing productive infection exhibit remarkable resistance to natural killer (NK) cell-mediated cytolysis in vitro.
To date, six genes encoding proteins (UL16, UL18, UL40, UL83, UL141 and UL142) and one encoding a microRNA (miR-UL112) have been identified as capable of suppressing NK cell recognition.
Even though HCMV infection efficiently activates expression of ligands for the NK cell activating receptor NKG2D, at least three functions (UL16, UL142 and miR-UL112) act in concert to suppress presentation of these ligands on the cell surface.
Although HCMV downregulates expression of endogenous MHC-I, it encodes an MHC-I homologue (UL18) and also upregulates the expression of cellular HLA-E through the action of UL40.
The disruption of normal intercellular connections exposes ligands for NK cell activating receptors on the cell surface, notably CD155.
HCMV overcomes this vulnerability by encoding a function (UL141) that acts post-translationally to suppress cell surface expression of CD155.
The mechanisms by which HCMV systematically evades (or, more properly, modulates) NK cell recognition constitutes an area of growing understanding that is enhancing our appreciation of the basic mechanisms of NK cell function in humans.
Keywords: Cytomegalovirus; NK cells
Corresponding Author Contact InformationCorresponding author at: Department of Medical Microbiology, Tenovus Building, Room 2F-03, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XY, UK. 1 Current address: Arrow Therapeutics, Britannia House, 7 Trinity Street, London SE1 1DB, UK.
Journal of Clinical Virology Volume 41, Issue 3, March 2008, Pages 206-212 CMV Special Issue, 11th International CMV and Beta Herpesvirus Workshop
-------------------- Note: I'm NOT a medical professional. The information I share is from my own personal research and experience. Please do not construe anything I share as medical advice, which should only be obtained from a licensed medical practitioner. Posts: 4881 | From Middlesex County, NJ | Registered: Jul 2006
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posted
Great stuff. Thanks for posting. You are a red hot researchin' mama!
Amazing how patients can do a better job with researching microbial diseases than the likes of the IDSA and the average infectious diseases doc.
Posts: 8430 | From Not available | Registered: Oct 2000
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posted
Got to wondering if the myeloid tissue had been investigated as a safe harbor for borrelia, like viral sites described above, and here is what a search of pubmed produced for myeloid +lyme search:
1:
Stewart PE, Wang X, Bueschel DM, Clifton DR, Grimm D, Tilly K, Carroll JA, Weis JJ, Rosa PA. Free in PMC Delineating the requirement for the Borrelia burgdorferi virulence factor OspC in the mammalian host. Infect Immun. 2006 Jun;74(6):3547-53. PMID: 16714587 [PubMed - indexed for MEDLINE]
2:
Bockenstedt LK, Liu N, Schwartz I, Fish D. Free in PMC MyD88 deficiency enhances acquisition and transmission of Borrelia burgdorferi by Ixodes scapularis ticks. Infect Immun. 2006 Apr;74(4):2154-60. PMID: 16552045 [PubMed - indexed for MEDLINE]
3:
Behera AK, Hildebrand E, Bronson RT, Perides G, Uematsu S, Akira S, Hu LT. Free in PMC MyD88 deficiency results in tissue-specific changes in cytokine induction and inflammation in interleukin-18-independent mice infected with Borrelia burgdorferi. Infect Immun. 2006 Mar;74(3):1462-70. PMID: 16495516 [PubMed - indexed for MEDLINE]
4:
Guerau-de-Arellano M, Huber BT. Abstract Chemokines and Toll-like receptors in Lyme disease pathogenesis. Trends Mol Med. 2005 Mar;11(3):114-20. Review. PMID: 15760769 [PubMed - indexed for MEDLINE]
5:
Lachowicz JL, Post GS, Moroff SD, Mooney SC. Abstract Acquired amegakaryocytic thrombocytopenia--four cases and a literature review. J Small Anim Pract. 2004 Oct;45(10):507-14. Review. PMID: 15515801 [PubMed - indexed for MEDLINE]
6:
Bolz DD, Sundsbak RS, Ma Y, Akira S, Kirschning CJ, Zachary JF, Weis JH, Weis JJ. Free Full Text MyD88 plays a unique role in host defense but not arthritis development in Lyme disease. J Immunol. 2004 Aug 1;173(3):2003-10. PMID: 15265935 [PubMed - indexed for MEDLINE]
7:
Liu N, Montgomery RR, Barthold SW, Bockenstedt LK. Free in PMC Myeloid differentiation antigen 88 deficiency impairs pathogen clearance but does not alter inflammation in Borrelia burgdorferi-infected mice. Infect Immun. 2004 Jun;72(6):3195-203. PMID: 15155621 [PubMed - indexed for MEDLINE]
8:
Pashenkov M, S�derstr�m M, Huang YM, Link H. Free in PMC Cerebrospinal fluid affects phenotype and functions of myeloid dendritic cells. Clin Exp Immunol. 2002 May;128(2):379-87. PMID: 11985531 [PubMed - indexed for MEDLINE]
9:
Pashenkov M, Teleshova N, Kouwenhoven M, Smirnova T, Jin YP, Kostulas V, Huang YM, Pinegin B, Boiko A, Link H. Abstract Recruitment of dendritic cells to the cerebrospinal fluid in bacterial neuroinfections. J Neuroimmunol. 2002 Jan;122(1-2):106-16. PMID: 11777549 [PubMed - indexed for MEDLINE]
10:
Bulut Y, Faure E, Thomas L, Equils O, Arditi M. Free Full Text Cooperation of Toll-like receptor 2 and 6 for cellular activation by soluble tuberculosis factor and Borrelia burgdorferi outer surface protein A lipoprotein: role of Toll-interacting protein and IL-1 receptor signaling molecules in Toll-like receptor 2 signaling. J Immunol. 2001 Jul 15;167(2):987-94. PMID: 11441107 [PubMed - indexed for MEDLINE]
11:
Pashenkov M, Huang YM, Kostulas V, Haglund M, S�derstr�m M, Link H. Free Full Text Two subsets of dendritic cells are present in human cerebrospinal fluid. Brain. 2001 Mar;124(Pt 3):480-92. PMID: 11222448 [PubMed - indexed for MEDLINE] Items 1 - 11 of 11
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AliG
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posted
Thanks Lou!
Funny thing, I was just thinking about that issue with IDs last night.
I think it has to do with the fact that we don't usually just die a horrible, tragic death within a couple of years. The ID's sense of urgency usually seems to lie with patients with the patients who have more dramatic diseases.
Our diseases seem tame to them, because they have not experienced how truly bizarre, frustrating, confusing & debilitating they can be.
We, on the other hand, find long, drawn-out pain, suffering and debilitation to be intolerable. Our need for faster answers tends to drive some of us to the point of obsession.
I believe that for most of those IDs, after a couple of years, being a specialized physician becomes a "job" and patients become viewed as something other than individual human beings.
I think that with the type of diseases they most often treat, they must "lose" a lot of patients. I believe that could cause emotional detachment.
It could be similar to the way labratory test animals become viewed as test-subjects, not animals, by researchers who are looking for answers. It's an emotional survival mechanism, one that doesn't work out so well for people with TBDs.
-------------------- Note: I'm NOT a medical professional. The information I share is from my own personal research and experience. Please do not construe anything I share as medical advice, which should only be obtained from a licensed medical practitioner. Posts: 4881 | From Middlesex County, NJ | Registered: Jul 2006
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AliG
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posted
Wow, THAT's really interesting!
I wasn't even thinking along THOSE lines.
I had read some of Timaca's posting about the Valcyte trials and had read the prescribing info on it.
I found that Valcyte has been used for Txing HCMV in AIDS patients (I'm not sure, but I think it may have been rushed to market for that purpose).
I then came across these articles this AM and thought, "Hmmmmm.....could latent HCMV become a problem when someone is infected with Bb? Could it take down the immune system, causing negative tests & making Bb more difficult to fight?"
-------------------- Note: I'm NOT a medical professional. The information I share is from my own personal research and experience. Please do not construe anything I share as medical advice, which should only be obtained from a licensed medical practitioner. Posts: 4881 | From Middlesex County, NJ | Registered: Jul 2006
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AliG
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Cytomegalovirus (CMV) is a very common virus that infects approximately one-half of all young adults in the United States.
It rarely causes serious consequences except in people with suppressed or impaired immune systems or in infants, whose immune systems are still developing.
The virus, a member of the herpesvirus family, is found in saliva, urine, and other bodily fluids. Because it is often found in semen as well as in cervical secretions, the virus can be spread by sexual contact; it also can be easily spread by other forms of physical contact such as kissing.
Day-care center staff for children under the age of 3 are at increased risk of CMV infection and should carefully wash their hands after changing diapers.
Like other herpesvirus infections, CMV is incurable; people are infected with it for life. Although the virus usually remains in an inactive state, it can reactivate from time to time.
Symptoms. In healthy adults, CMV usually produces no symptoms of infection. Occasionally, however, mild symptoms of swollen lymph glands, fever, and fatigue may occur. These symptoms may be similar to those of infectious mononucleosis.
Diagnosis. The ELISA (enzyme-linked immunosorbent assay) test is commonly used to detect levels of antibodies (disease-fighting proteins of the immune system) in the blood.
A number of other blood tests can suggest a diagnosis of CMV infection, but no blood test can reliably diagnose it.
Although CMV can be isolated from urine or other body fluids, it may be excreted months or years after an infection; therefore, isolation of the virus from these fluids is not a reliable method of diagnosing recent infection.
Complications. Babies can be infected with CMV in the uterus if their mothers become infected with the virus or develop a recurrence of a previous infection during pregnancy.
Although most babies infected with CMV before birth do not develop any symptoms, CMV is the leading cause of congenital infection in the United States.
An estimated 6,000 babies each year develop life-threatening complications of congenital CMV infection at birth or suffer serious consequences later in life, including mental retardation, blindness, deafness, or epilepsy.
Investigators supported by NIAID are currently studying how the virus interferes with normal fetal development and at which stages the fetus is most susceptible to infection. Congenital CMV is the most common cause of progressive deafness in children.
When CMV is acquired after birth, or if it reactivates, it can be life-threatening for persons with suppressed immune systems, such as those receiving chemotherapy or persons who have received immunosuppressant drugs for organ transplantation.
Persons with HIV infection or AIDS may develop severe CMV infections, including CMV retinitis, an eye disease that can lead to blindness.
Treatment. NIAID scientists are testing new antiviral drugs that might be effective against CMV infections.
The antiviral drugs foscarnet and ganciclovir have been approved for treating people with AIDS-associated CMV retinitis.
Prevention. There is no intervention to prevent CMV. Use of the male condom may reduce risk although virus in the saliva would be transmitted by kissing or oral intercourse.
Some experts believe that primary or first-time exposure during pregnancy is a major cause of CMV infection in newborns.
Infants infected before or just after birth are likely to be shedding CMV in saliva and urine, which can infect others.
Hand washing and proper handling of diapers may reduce risk.
Scientists are working to develop a vaccine and other methods to provide immunity to CMV and offer protection against severe disease.
-------------------- Note: I'm NOT a medical professional. The information I share is from my own personal research and experience. Please do not construe anything I share as medical advice, which should only be obtained from a licensed medical practitioner. Posts: 4881 | From Middlesex County, NJ | Registered: Jul 2006
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