Human endogenous retrovirus K (HERV-K) env in neuronal extracellular vesicles: a new biomarker of motor neuron disease

Li, Yuan; Chen, Yong; Zhang, Nan

doi:10.1080/21678421.2021.1936061

Cited by 14 publications

(16 citation statements)

References 40 publications

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“…Although coronavirus can evade and inhibit the IFN response to achieve high pathogenicity [ 39 , 40 , 41 , 42 , 43 ], much evidence has shown that IFN-I and IFN-III still have the potential to treat SARS, MERS, and COVID-19 [ 44 , 45 , 46 , 47 , 48 , 49 , 50 ]. As a HERV family closely related to the growth and development of the host, HERV-K is often related to the abnormal activation of diseases, and many biomarkers of disease take this as the development point [ 26 , 51 , 52 ]. In this study, we confirmed that the activation of HERV-K leads to the activation of the IFN pathway, which provides a new direction for the potential mechanism of interferon production; at the same time, it also provides a new view of the physiological function of HERV-K. We think that when disease occurs, HERV-K participates in the regulation of immunity and accelerates the recovery from disease.…”

Section: Discussionmentioning

confidence: 99%

High Expression of HERV-K (HML-2) Might Stimulate Interferon in COVID-19 Patients

Guo

Yang

Liu

et al. 2022

Viruses

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Background. Interferon is a marker of host antiviral immunity, which is disordered in COVID-19 patients. ERV can affect the secretion of interferon through the cGAS-STING pathway. In this study, we explored whether IFN-I and HERV-K (HML-2) were activated in COVID-19 patients and whether there was an interaction between them. Methods. We collected blood samples from COVID-19 patients and healthy controls. We first detected the expression of HERV-K (HML-2) gag, env, and pol genes and IFN-I-related genes between patients and healthy people by qPCR, synchronously detected VERO cells infected with SARS-CoV-2. Then, the chromosome distributions of highly expressed HERV-K (HML-2) gag, env, and pol genes were mapped by the next-generation sequencing results, and GO analysis was performed on the related genes. Results. We found that the HERV-K (HML-2) gag, env, and pol genes were highly expressed in COVID-19 patients and VERO cells infected with SARS-CoV-2. The interferon-related genes IFNB1, ISG15, and IFIT1 were also activated in COVID-19 patients, and GO analysis showed that HERV-K (HML-2) can regulate the secretion of interferon. Conclusions. The high expression of HERV-K (HML-2) might activate the increase of interferon in COVID-19 patients, proving that HERV-K does not only play a negative role in the human body.

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Section: Discussionmentioning

confidence: 99%

High Expression of HERV-K (HML-2) Might Stimulate Interferon in COVID-19 Patients

Guo

Yang

Liu

et al. 2022

Viruses

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“…Furthermore, transgenic mice that expressed the Env under a neuronal promoter developed an ALS-like syndrome with exclusive degeneration of the upper and lower motor neurons [22]. Other groups have reproduced the discovery of HERV-K activation in individuals with ALS [58,59] although the activation may not be specific for ALS [24,25]. HERV-K (HML-2) activation has also been seen in individuals with frontotemporal dementia [58] (Fig.…”

Section: Detection Of Reverse Transcriptase Activity In Alsmentioning

confidence: 99%

“…Since DNA is stable, it can be easily measured quantitatively by droplet digital PCR in serum, plasma or CSF but needs to be distinguished from chromosomal copies of the viral genes [120]. HML-2 Env protein can also be measured using immunoprecipitation or a sandwich ELISA [59]. Specific epitopes have been identified on the HML-2 Env protein to which ALS patients develop antibodies [62].…”

Section: Monitoring Of Hml-2 In Patients With Alsmentioning

confidence: 99%

Retroviral Elements in Pathophysiology and as Therapeutic Targets for Amyotrophic Lateral Sclerosis

Pandya

Pasternack

et al. 2022

Neurotherapeutics

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The study of the role of retroviruses in amyotrophic lateral sclerosis (ALS) dates back to the 1960s shortly after transposable elements themselves were first discovered. It was quickly realized that in wild mice both horizontal and vertical transmissions of retroviral elements were key to the development of an ALS-like syndrome leading to the postulate that endogenous retroviruses (ERVs) contribute significantly to the pathogenicity of this disease. Subsequent studies identified retroviral reverse transcriptase activity in brains of individuals with ALS from Guam. However, except for a single study from the former Soviet Union, ALS could not be transmitted to rhesus macaques. The discovery of an ALS-like syndrome in human immunodeficiency virus (HIV) and human T cell leukemia virus infected individuals led to renewed interest in the field and reverse transcriptase activity was found in the blood and cerebrospinal fluid of individuals with sporadic ALS. However, exogenous retroviruses could not be found in individuals with ALS which further reinforced the possibility of involvement of a human ERV (HERV). The first demonstration of the involvement of a HERV was the discovery of the activation of human endogenous retrovirus-K subtype HML-2 in the brains of individuals with ALS. The envelope protein of HML-2 is neurotoxic and transgenic animals expressing the envelope protein develop an ALS-like syndrome. Activation of HML-2 occurs in the context of generalized transposable element activation and is not specific for ALS. Individuals with HIV-associated ALS show a remarkable response to antiretroviral therapy; however, antiretroviral trials in ALS down-regulate HML-2 without ameliorating the disease. This highlights the need for specific drugs to be developed against HML-2 as a novel therapeutic target for ALS. Other approaches might include antisense oligonucleotides, shRNA targeted against the envelope gene or antibodies that can target the extracellular envelope protein. Future clinical trials in ALS should consider combination therapies to control these ERVs.

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“…High levels of expression of HML‐2 have been found in autopsied brain samples from subsets of individuals with ALS 12, 13 . In one study HML‐2 envelope (env) protein was detected in plasma‐derived extracellular vesicles with higher levels in advanced stages of the illness 14 . Expression of the env protein in neurons triggers neurodegeneration in vitro and motor neuron disease in a transgenic mouse model 12 .…”

Section: Introductionmentioning

confidence: 99%

“… 12 , 13 In one study HML‐2 envelope (env) protein was detected in plasma‐derived extracellular vesicles with higher levels in advanced stages of the illness. 14 Expression of the env protein in neurons triggers neurodegeneration in vitro and motor neuron disease in a transgenic mouse model. 12 In an open label study, reduction of HML‐2 viral load in serum of individuals with ALS treated with anti‐retroviral therapy was associated with a slower clinical progression.…”

Section: Introductionmentioning

confidence: 99%

Antibody Response to HML‐2 May Be Protective in Amyotrophic Lateral Sclerosis

García-Montojo

Simula

Fathi

et al. 2022

Annals of Neurology

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Objectives Reactivation of HERV‐K(HML‐2) has been found in subsets of individuals with amyotrophic lateral sclerosis (ALS). This study examines the antibody response against HML‐2 in ALS and analyzes its clinical relevance. Methods Antibodies to HML‐2 envelope (env) were analyzed using a peptide array for epitope mapping and by a peptide enzyme‐linked immunosorbent assay (ELISA) in 242 healthy donors, and 243 ALS and 85 multiple sclerosis (MS) individuals. Extracellular levels of HML‐2 were analyzed by digital polymerase chain reaction (PCR). Results Antibodies in the sera of ALS individuals recognized more HML‐2 env peptides compared to healthy controls (p < 0.0001). ALS individuals had higher levels of HML‐2 than healthy donors (p = 0.02) and higher antibody levels against a select HML‐2 env peptide compared to healthy donors or individuals with multiple sclerosis (p < 0.0001). 55.14% of ALS compared to 21.16% of healthy donors and 13.10% of MS individuals had antibodies against the HML‐2 peptide (AUC = 0.769, p < 0.0001). Levels of extracellular HML‐2 DNA in serum (p = 0.02) and the number of HML‐2 env peptides recognized by ALS sera (p = 0.02) correlated with disease duration. Among ALS individuals, lower levels of HML‐2 antibodies were associated with a definite diagnosis per EL Escorial criteria (p = 0.03), and with a lower predicted (p = 0.02) and observed survival (p = 0.03). Interpretation There is a differential antibody response against specific epitopes of HML‐2 env in ALS and controls, suggesting epitope spreading, likely due to persistent antigenic exposure following reactivation of the viral genes. Low levels of antibodies to HML‐2 env in ALS are associated with poor prognosis and decreased survival probability. ANN NEUROL 2022;92:782–792

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Human endogenous retrovirus K (HERV-K) env in neuronal extracellular vesicles: a new biomarker of motor neuron disease

Cited by 14 publications

References 40 publications

High Expression of HERV-K (HML-2) Might Stimulate Interferon in COVID-19 Patients

High Expression of HERV-K (HML-2) Might Stimulate Interferon in COVID-19 Patients

Retroviral Elements in Pathophysiology and as Therapeutic Targets for Amyotrophic Lateral Sclerosis

Antibody Response to HML‐2 May Be Protective in Amyotrophic Lateral Sclerosis

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