Human Endogenous Retrovirus W Family and its Association with Schizophrenia: More Research Is Warranted

Human endogenous retroviruses (HERVs), particularly those belonging to the W family, HERV-W, are one focus of research on factors that may be implicated in causing schizophrenia (SCZ) or promoting its development over time. HERVs are part of the human genome and are passed from parents to their offspring. There are hundreds of different types of HERVs in our DNA and together they make up roughly 8% of the human genome. It is not yet known what roles they play in health or disease, with one exception. A member of the HERV-W family, ERVWE-1, that produces the protein called syncytin-1, plays a role in the normal formation of the placenta (1). There are many potential links between HERV-W and SCZ, so I will provide an overview here of the evidence that is consistent with the hypothesis that HERV-W activation contributes to the development of SCZ.

To date, associations have been made between HERV-W activity and SCZ, but it is impossible to determine whether it plays a part in causation or is a response to the condition (2).

In particular, several studies have detected evidence of HERV-W activity in SCZ in significant portions of people with the disease, compared to healthy controls, but also in bipolar disorder, and by no means in all people with SZC studied (2,3). Another question is, therefore, whether members of the HERV-W family are associated with SCZ in a subgroup of patients only, or if limitations of these studies resulted in a failure to detect HERV activity in the vast majority of patients (3).

There are a number of reasons why the hypothesis that HERV-W plays a crucial role in the development and course of SZC is an attractive one. Evidence of HERV-W activity, such as the detection of its proteins, mRNAs (a given mRNA is the blueprint for manufacturing a specific protein), or antibody to HERV-W proteins, has been observed in a substantial portion of SCZ patients studied, as mentioned above.

Observations have also been made about features of schizophrenia that are consistent with activity on the part of HERV-W, but by no means has any direct association been established between them.

HERV-Ws are activated by some of the microbes associated with SCZ, such as influenza A  and T. gondii, a kind of parasite(4). Prenatal maternal infections (infections of pregnant women potentially affecting the unborn child) by these infectious agents are known to be associated with SCZ. Also, infections with cytomegalovirus and T. gondiilater in life are minor risk factors for schizophrenia. This has ledsome experts to consider that members of the HERV-W family may be activated in the fetus, triggering changes in brain development that may eventually lead to SCZ later, if other factors contributing to the disease are also present, such as genetic background and exposure to adversity or other infectious agents in childhood, adolescence and early adulthood.

The envelope protein (env) of one member of the HERV-W family, the multiple sclerosis-associated retrovirus, MRSV, is known to stimulate cells of the immune system to promote an inflammatory response (5). Low-grade inflammation is also characteristic of SCZ (6). In particular, env stimulates Toll-like receptor 4, a protein on cell surfaces that triggers what is called innate immunity. In turn, this causes the production of cytokines, proteins that modulate immune responses, particularly one called IL-6, whose levels are known to be altered in SCZ (6).

It “remains to be proven whether there is any overlap between patients with HERV expression, subsets of patients with infectious associations, and those with raised inflammatory markers. This would make sense given the existing evidence, but further experimental evidence is now required”(4).

HERV-W is known to affect the production of the protein called brain-derived neurotrophic factor, BDNF, whose activity is also associated with SCZ(7). In turn, BDNF modulates levels of the protein called dopamine receptor D3, DRD3, a receptor for the neurotransmitter dopamine. Neurotransmitters are the chemical substances that transmit nerve impulses.The interaction of BDNF and DRD3 is associated with the early occurrence of psychosis in SCZ (3).

In addition,HERV-W env protein binds neutral amino acid transporters (ASCT-1 and ASCT-2) present on brain cells, including neurons (9). The binding of HERV-W env could potentially block the production of neurotransmitters in cells where ASCT1 and ASCT2 are bound by HERV-W env protein. Alterations in the pathway of the neurotransmitter dopamine is a hallmark of schizophrenia, and while the link between dopamine production and HERV-W activity is remote, HERV-W activity as a contributing factor to alterations of the pathway is plausible.

Copies of HERV-W DNA occupy locations in human DNA close to genes associated with SCZ, such as the receptor for the neurotransmitter GABA, GABA receptor B 1, and could potentially alter its activity (2).

If HERV-W elements cause deletions and modifications of DNA, as other HERVs do (8), the effect exerted on DNA may explain changes in DNA that are associated with SCZ. International Schizophrenia Consortium (10).

The variety of HERV-W family members is presently a barrier to defining the precise identity of the types of HERV-W that may be involved in SCZ, since they have not been studied in enough detail and were not distinguishable from each other in most previous studies. Several different members of the HERV-W family could have been detected by the methods used, including the better characterized multiple sclerosis-associated retrovirus (MRSV) and ERVWE-1, in both mRNA and protein analyses (8). Clearly, methods that can make these distinctions are needed in order to pinpoint the specific HERV-Ws that are active in SCZ. Estimates vary, but there may be over 300 members of the HERV-W family, only some of which have the capability to produce their own mRNA and proteins (8).

While there is no proof that members of the HERV-W family drive the above-mentioned SCZ-associated factors during the disease or in the course of events leading up to it, it is tempting to consider that HERV-W activity may be the hub that links these disparate factors associated with SCZ, which, by acting together, could be responsible for producing the disease.

Ellul and colleagues have put forward the hypothesis that HERV-W activation triggered by prenatal maternal infections may lay the groundwork for the evolution to schizophrenia in late adolescence or early adulthood, when they propose that a second activation of HERV-W, also due to infection by an external agent, triggers the onset of overt signs and symptoms (3). This framework is consistent with the emerging view that “a multifactorial conceptualization of psychiatric disease in which multiple biologically significant events (or “hits”) are temporally distributed across early periods of the overall lifespan, and result in the development of schizophrenia-like diseases.” (11). Both are consistent with the two-hit hypothesis of schizophrenia that suggests that a combination of genetic susceptibility coupled with a distinct developmental insult can prime an individual for a later event that ultimately leads to the onset of the full clinical syndrome (11).

Undoubtedly, SCZ causation is complex and more research on its genetic, immunological, microbiological, and neurological features is needed to shed light on it. Research on the role members of the HERV-W family may play is certainly worthwhile and could lead to novel therapies and diagnostic tools for SCZ.  At the very least, the characterization of HERV-W activity in people with SCZ could give rise to the identification of biomarkers that distinguish subgroups of patients from each other and thereby introduce targeted therapy into the treatment and management of people with SCZ, in itself a very meaningful step forward.

  1. Frendo J-L, Olivier D, Cheynet V, Blond J-L, Bouton O, Vidaud M, et al. Direct Involvement of HERV-W Env Glycoprotein in Human Trophoblast Cell Fusion and Differentiation. Mol Cell Biol. 2003 May 15;23(10):3566–74.
  2. Slokar G, Hasler G. Human Endogenous Retroviruses as Pathogenic Factors in the Development of Schizophrenia. Front Psychiatry [Internet]. 2016 Jan 11 [cited 2016 Jul 24];6. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4707225/
  3. Ellul P, Groc L, Leboyer M. Les rétrovirus endogènes humains, une implication dans la schizophrénie et le trouble bipolaire. médecine/sciences. 2017 Apr;33(4):404–9.
  4. Aftab A, Shah AA, Hashmi AM. Pathophysiological Role of HERV-W in Schizophrenia. J Neuropsychiatry Clin Neurosci. 2016;28(1):17–25.
  5. Rolland A, Jouvin-Marche E, Viret C, Faure M, Perron H, Marche PN. The Envelope Protein of a Human Endogenous Retrovirus-W Family Activates Innate Immunity through CD14/TLR4 and Promotes Th1-Like Responses. J Immunol. 2006 Jun 15;176(12):7636–44.
  6. Leboyer M, Oliveira J, Tamouza R, Groc L. Is it time for immunopsychiatry in psychotic disorders? Psychopharmacology (Berl). 2016 May;233(9):1651–60.
  7. Huang W, Li S, Hu Y, Yu H, Luo F, Zhang Q, et al. Implication of the env Gene of the Human Endogenous Retrovirus W Family in the Expression of BDNF and DRD3 and Development of Recent-Onset Schizophrenia. Schizophr Bull. 2011 Sep;37(5):988–1000.
  8. Morandi E, Tanasescu R, Tarlinton RE, Constantinescu CS, Zhang W, Tench C, et al. The association between human endogenous retroviruses and multiple sclerosis: A systematic review and meta-analysis. PLOS ONE. 2017 Feb 16;12(2):e0172415.
  9. Marin M, Lavillette D, Kelly SM, Kabat D. N-Linked Glycosylation and Sequence Changes in a Critical Negative Control Region of the ASCT1 and ASCT2 Neutral Amino Acid Transporters Determine Their Retroviral Receptor Functions. J Virol. 2003 Mar 1;77(5):2936–45.
  10. The International Schizophrenia Consortium. Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature. 2008 Sep;455(7210):237–41.
  11. Feigenson KA, Kusnecov AW, Silverstein SM. Inflammation and the two-hit hypothesis of schizophrenia. Neurosci Biobehav Rev. 2014 Jan;38:72–93.

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PLoS Computational Biology Issue Image, Vol. 6(8) August 2010. PLoS Comput Biol 6(8): ev06.i08. doi:10.1371/image.pcbi.v06.i08
Hermann Cuntz

 

 

 

 

 

 

 

 

 

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