Can depression, psychiatric disorders and fatigue be triggered by a neurovirulent latent HHV-6B protein?

Three virologists led by Kazuhiro Kondo, MD, PhD, a professor of virology at Jikei University School of Medicine, have filed a patent on a method to diagnose, treat and prevent mood disorders which he says are initiated by neurovirulent “latent” HHV-6B residing in glial cells, and that this condition can be treated effectively with nasal sprays, using the olfactory nerve as a route to the brain. The method is reliant on the measurement of anti-SITH-1 antibodies. SITH-1, or “small protein encoded by intermediate state transcript,” is so named by Dr. Kondo, and it is produced via expression of an HHV-6 latency-associated gene.

Kazuhiro Kondo, MD, PhD, Professor, Department of Virology, The Jikei University School of Medicine

The patent claim states that when HHV-6B SITH-1 is produced, it results in the up-regulation of several depression-related factors relating to stress hormones. Kondo and his associates showed evidence that anti-SITH-1 antibodies were found at higher concentrations in patients with depression, psychiatric disorders, and chronic fatigue syndrome. They also demonstrated that by inserting the SITH-1 gene into an adenoviral vector and introducing it to a mouse, they can induce depressive symptoms.

A number of viruses, including herpes simplex-1, adenovirus, West Nile virus, and influenza type A, use the olfactory nerve as a shortcut to the brain. A recent study by NINDS researcher Steve Jacobson showed that HHV-6 could travel through the brain via the olfactory route and also found that the olfactory bulb is an important reservoir for latent HHV-6 (Harberts 2011). Olfactory dysfunction also occurs in a number of neurological conditions such as myasthenia gravis, Parkinson’s disease, Alzheimer’s and MS. Kondo plans to utilize this pathway using a nasal spray as a means of getting their treatment to the brain.

Treatments covered in the patent include heparin, which has recently been suggested to have antiviral properties (Dogra 2015, Mulloy 2016), interfering RNA such as siRNA or miRNA or attenuated HHV-6 vaccines.

Kondo commented that even though current antiviral therapies are ineffective against the “latent” virus that triggers CNS dysfunction, extended antiviral therapy can still be helpful because the virus reactivates intermittently:  “The life span of the cells in which HHV-6 establishes latency is not very long; to maintain life long latency, the virus must be reactivated and move to other young cells,” said Kondo.

The patent proposes that administering a vaccine into the nasal mucosa will generate-HHV-6 IgA antibodies in the nasal secretions, which will help to control HHV-6. The nasal vaccine that the group proposes contains inactivated virion antigen in a hydrophilic cationic “nano gel”.

Kondo published a study on HHV-6 and fatigue in 2005, proposing that HHV-6 DNA in the saliva is an objective biomarker for fatigue. He noted that 88% of stressed office workers shed reactivated HHV-6 in the saliva right before the holidays, but only 23% shed HHV-6 just after the holidays (Kondo 2005).

In 2008, Kondo presented an abstract demonstrating that when the HHV-6B SITH-1 protein was transfected into the glial cells of mice, the mice developed “manic” behavior. He also reported that over half of depressed patients and three quarters of bipolar patients were positive for anti SITH-1 antibodies. (Abstract, 6th International Conference on HHV-6 & 7).

Kondo noted that he is still working to make the SITH-1 antibody assay more sensitive and that his work (still unpublished) has been challenging. He explained that developing an antibody assay was necessary because “there is no detectable DNA in the plasma” in these low level persistent infections.

The proteins they say are triggered by HHV-6B latency are corticotropin releasing hormone, urocortin, and REDD1 (an acronym for “regulated in development DNA responses-1”) in the hypothalamus. REDD-1 is increased in the prefrontal cortex in autopsy samples from patients with major depression (Ota 2014), and urocortins play a role in regulating anxiety and social behavior. SITH-1 production, they say, also results in increased intracellular calcium levels, a common finding in depression and psychiatric disorders.

REDD1 is an inhibitor of mTORC1 (mammalian target of rapamycin complex 1), and mTORC1 signaling is decreased in depression. A recent study at Yale showed that rodents exposed to chronic unpredictable stress have increased levels of REDD1 in the prefrontal cortex. Furthermore, REDD1-knockout mice do not show the synaptic, behavioral, or mTORC1-signaling deficits caused by chronic stress, while rodents with viral-mediated overexpression of REDD1 demonstrated neuronal atrophy and symptoms of depression and anxiety. (Ota 2014)

Corticotropin releasing hormone (CRH) is part of the hypothalamic-pituitary-adrenal (HPA) axis, which controls and regulates reactions to stress and other body processes (Vale 1981). Previous studies have shown elevated concentrations of CRH in the plasma, CSF, and multiple brain regions in individuals with depression (Waters 2015). An increase in behaviors associated with stress-mediated pathology, such as anxiety, anhedonia, and decreased appetite, has been observed in multiple studies where rodents were injected with CRH.

CRH is part of the corticotropin-releasing factor family, which also includes urocortins 1, 2, and 3 (Ucn 1, 2, and 3, respectively), and binds to CRH receptors 1 and 2 (CRH-1, CRH-2). Sustained stimulation of CRH-1 is believed to play a role in depressive disorders (Rakosi 2014), and CRH-1 knockout mice have exhibited diminished responses to stress (Waters 2015).

Dr. Kondo first described HHV-6 latency in monocytes in 1991 while a graduate student in the laboratory of Koichi Yamanishi at Osaka University. Dr. Yamanishi was the first to show that HHV-6B was the cause of roseola in infants.

Dr. Kondo and colleagues have been granted a number of patents over the past ten years, including one on a method of diagnosing fatigue (by measuring HHV-6B DNA load in the saliva), a method of diagnosing mood disorders (by measuring HHV-6 markers), and a method of using HHV-6 as a vector for therapeutic agents. Links to the patents and the two most recent patent applications are below. The research findings were developed through a biotechnology collaboration with Japan Tobacco.

Patent Applications:

December 2015 Method for diagnosing, treating, or preventing mood disorder (WO 2015199247 A1)

January 2013: Factor involved in latent infection with herpesvirus, and use thereof US 2013021704 (WO2009041501A1,)

Patents granted:

March 2010 Method for detecting antibody against sith-1 in biological sample US9139617B2 (WO2010114029A1,)

September 2008 Diagnosis of mood disorders by detecting latent infection with human herpesvirus-6 US 8431352 B2 (WO2009041501A1)

July 2005 Methods for assessing fatigue level and applications thereof
US 7824888 B2

2004   Recombinant virus vector originating in hhv-6 or hhv-7, method of producing the same, method of transforming host cell using the same, host cell transformed thereby and gene therapy method using the same
US8642045B2 (WO2005021746A1)