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Whatever happened to... research on SITH-1 protein made by HHV-6 in ME/CFS patients

Hip

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Whatever happened to... the new research on SITH-1 protein made by HHV-6?

SITH-1 protein was found in many ME/CFS patients, but not at all in healthy controls. Cort's article of May 2008 on this SITH-1 protein is here.

Dr Kazuhiro Kondo discovered this new SITH-1 protein made by HHV-6, and his work indicates that SITH-1 may cause the psychological symptoms (mood disorders) of ME/CFS, major depression, and bipolar disorder. SITH-1 significantly up-regulates intracellular calcium levels. Increase of calcium level in the brain tissue is generally considered the most important cause of psychological disorders.


Kondo thinks that this disruptive SITH-1 protein is created under a special type of HHV-6 latency. Kondo's hypothesis is that HHV-6 has at least three forms of latency:

Latency type I in healthy adults, where the virus is under control.
Latency type II restricted reactivation (in astrocytes) is when SITH-1 is made and causes ME/CFS?
Latency type III the normal virus reactivation.

Kondo's hypothesis is that the restricted form of HHV-6 latency (latency type II) leads to ME/CFS.

I have had a good look round online, but have not found all that many updates on this seemingly very significant research by Dr Kondo. Here's all I found:

March 2010, a patent was filed:
METHOD FOR DETECTING ANTIBODY AGAINST SITH-1 IN BIOLOGICAL SAMPLE.
September 2010, Dr Kazuhiro Kondo gave a presentation in Japan:
Identification of a novel HHV-6 latent-protein associated with CFS and mood disorders.

This line of inquiry into SITH-1 seem to be fairly low key, in spite of its apparent groundbreaking implications.


Some more info on SITH-1:

Kondo identified a novel HHV-6 protein associated with latent (non-replicating) HHV-6-infected nervous system and immune cells. Transfecting this new protein, called SITH-1 (Small Intermediate Stage Transcript of HHV-6), into nervous system cells called glial cells resulted in greatly increased intracellular calcium levels. Increased intracellular calcium levels are believed to play an important role in psychological disorders and can contribute to cell death.

Expressing the SITH protein though the use of an adenoviral vector in mouse resulted in manic-like behavior.

A serological study indicated that 71% of CFS patients with psychological symptoms - and none of the healthy controls - possessed the antibody against the SITH-1 protein.

Further tests indicated that 53% of depression and 76% of bipolar depression patients possessed the antibody.

http://www.prohealth.com/library/showarticle.cfm?id=8946&t=CFIDS_FM


Intriguingly the SITH-1 protein is produced when HHV-6 is latent. Latency, it turns out, is a something of a misnomer; it simply means the virus is not replicating and eventually killing the cell and then spilling its virions by the millions into the bloodstream. Kondos study bears witness to the fact that viruses can be engaged in all sorts of damaging activities (such as generating damaging cytokines) that researchers have basically ignored. (A latent central nervous system virus ,for instance, could prompt cells to produce immune agents called cytokines that are able to cause the kinds of symptoms found in ME/CFS).

Source: here.


Identification of novel HHV-6 neurovirulent latent protein that causes mood disorders in CFS, psychosis and HHV-6 encephalopathy

Nobuyuki Kobayashi, Kazuya Shimada, Hirohiko Kuratsune, and Kazuhiro Kondo.

Objective: Human herpesvirus 6 (HHV-6) has exhibited the most promise as a candidate for a Chronic fatigue syndrome (CFS)-associated virus. In the present study we have aimed at identifying the HHV-6 protein responsible for CFS, and proved that the newly identified HHV-6 protein causes mood disorders in CFS and psychosis.

Methods: We have searched for unidentified HHV-6 latency-associated transcripts and proteins in the latently infected macrophages and glial cells. Subsequently, we have analyzed the function of newly identified latency-associated protein. Moreover, we have studied the expression of the protein by examining the prevalence of antibody against the protein among patients (CFS, psychosis etc) and healthy individuals.

Results: We identified the novel HHV-6 latent transcript that was expressed during the relatively activated latent stage (intermediate stage) of HHV-6 latency. This transcript encoded the small open reading frame, which we named Small protein encoded by the Intermediate stage Transcript of HHV-6 (SITH-1). When we transfect SITH-1 into glial cells, it significantly up-regulated the intracellular calcium levels. Increase of calcium level in the brain tissue is generally thought to be the most important cause of psychological disorders. When we expressed SITH-1 in the mouse brain glial cells by using adenovirus vector, the mouse showed manic-like behavior in several behavior tests.

In the serological study, no healthy adults possessed the antibody against the HHV-6 latent protein SITH-1. However, in the CFS patients who had psychological symptoms, 71% of the patients possessed the antibody against SITH-1. In addition, 53% of depression patients and 76% of bipolar depression patients were positive for antibody against SITH-1.

Furthermore, mRNA encoding SITH-1 was detected in the autopsy brain tissue of patients who had mood disorders as sequelae of HHV-6 encephalitis.

Conclusion: We have identified the novel HHV-6 latent protein SITH-1, which may cause mood disorders in CFS and psychosis.

Discussion: Causes of many chronic diseases are unknown, and chronic viral infection is one of the most suspected candidates. In this study we show that HHV-6 that establishes latency in the brain glial cells can cause mood disorders via newly identified HHV-6 latent protein SITH-1.

http://www.scivee.tv/assets/files/6833/kondo.pdf


Kazuhiro Kondo, Md, Phd, Jikei University School of Medicine, Tokyo.

Kazuhiro Kondo is Professor and Chairman of the Department of Virology at the Jikei university School of Medicine in Tokyo. He is internationally recognized as one of the top experts on HHV-6 molecular biology. His research focuses on the role of HHV-6 in latency associated genes and the role of HHV-6 & 7 in CFS and other states of fatigue. In a recent study he found that HHV-6 and HHV-7 reactivation in the saliva can be used as objective biomarkers for fatigue. His latest work involves the identification of a novel HHV-6 neurovirulent latent protein that he can cause mood disorders in CFS, psychosis and HHV-6 encephalopathy.

http://www.iacfsme.org/Portals/0/pdf/HHV6SatBroch08.pdf


Video Presentation on SITH-1 by Dr Kazuhiro Kondo:

Kazuhiro Kondo (HHV-6 & 7 in CNS Dysfunction Video Session)
6th International Conference on HHV-6 & 7 in Baltimore, Maryland, USA.
June 22, 2008 - HHV-6 & 7 in CNS Dysfunction Session.

Some notes from the video:

HHV-6 establishes a latent infection in astrocyte cells in the brain.

In mouse model: SITH-1 gene expression was driven by astrocyte specific GFAP promoter.

SITH-1 alters intracellular calcium levels and causes mood disorders.

Kondo's hypothesis is that HHV-6 has at least three forms of latency:
Latency type I in healthy adults, where the virus is under control.
Latency type II restricted reactivation (in astrocytes) is when SITH-1 is made and causes ME/CFS?
Latency type III the normal virus reactivation.

Kondo's hypothesis is that the restricted form of HHV-6 latency (latency type II) leads to ME/CFS.
 
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Hip

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Interesting. So could hhv6/b be one of the key players?
HHV-6A and HHV-6B have long been associated with ME/CFS, so it is nothing new to assume that HHV-6 may be underpinning some subsets of ME/CFS.

What is new is that Dr Kazuhiro Kondo is exploring a particular HHV-6-driven mechanism (namely, the synthesis of SITH-1 protein during HHV-6 latency) which he thinks may be responsible for the symptoms of ME/CFS, as well as the symptoms of other conditions such as depression and bipolar disorder.