Inhibition of HERV-K (HML-2) in amyotrophic lateral sclerosis patients on antiretroviral therapy

García-Montojo, Marta; Fathi, Saeed; Norato, Gina; Smith, Bryan; Rowe, Dominic B.; Kiernan, Matthew C.; Vucic, Steve; Mathers, Susan; Eijk, Ruben P A van; Santamaria, Ulisses A.; Rogers, Mary‐Louise; Malaspina, Andrea; Lombardi, Vittoria; Mehta, Pritesh; Westeneng, Henk‐Jan; Berg, Leonard H van den; Al‐Chalabi, Ammar; Gold, Julian; Nath, Avindra

doi:10.1016/j.jns.2021.117358

Cited by 35 publications

(29 citation statements)

References 32 publications

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“…Studies exist where effects of abacavir or AZT in cells or animals could be attributed to HERV-K RT. For example, the current clinical trial in ALS using Triumeq (abacavir, 3TC, and dolutegravir) ( 68 ) could plausibly provide HERV-K RT-mediated effects via inhibition by abacavir, but not 3TC. We find that 3TC is a poor inhibitor of HERV-K RT, in contrast to its potent HIV-1 RT inhibitory activity.…”

Section: Discussionmentioning

confidence: 99%

Human endogenous retrovirus-K (HERV-K) reverse transcriptase (RT) structure and biochemistry reveals remarkable similarities to HIV-1 RT and opportunities for HERV-K–specific inhibition

Baldwin¹,

Götte

Tchesnokov

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Human endogenous retroviruses (HERVs) comprise nearly 8% of the human genome and are derived from ancient integrations of retroviruses into the germline. The biology of HERVs is poorly defined, but there is accumulating evidence supporting pathological roles in diverse diseases, such as cancer, autoimmune, and neurodegenerative diseases. Functional proteins are produced by HERV-encoded genes, including reverse transcriptases (RTs), which could be a contributor to the pathology attributed to aberrant HERV-K expression. To facilitate the discovery and development of HERV-K RT potent and selective inhibitors, we expressed active HERV-K RT and determined the crystal structure of a ternary complex of this enzyme with a double-stranded DNA substrate. We demonstrate a range of RT inhibition with antiretroviral nucleotide analogs, while classic nonnucleoside analogs do not inhibit HERV-K RT. Detailed comparisons of HERV-K RT with other known RTs demonstrate similarities to diverse RT families and a striking similarity to the HIV-1 RT asymmetric heterodimer. Our analysis further reveals opportunities for selective HERV-K RT inhibition.

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Section: Discussionmentioning

confidence: 99%

Human endogenous retrovirus-K (HERV-K) reverse transcriptase (RT) structure and biochemistry reveals remarkable similarities to HIV-1 RT and opportunities for HERV-K–specific inhibition

Baldwin¹,

Götte

Tchesnokov

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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“…The one protein shared by LINE-1 and HERVs, and to which they owe their name, is the RT. Several FDA-approved drugs used in AIDS (acquired immunodeficiency syndrome) therapies that target HIV (human immunodeficiency virus) RT also efficiently inhibit the RT enzymes of LINE-1 ( Dai et al, 2014 ; Krug et al, 2017 ; Liu et al, 2019 ) and the RT of HERVs ( Garcia-Montojo et al, 2021 ). Blocking LINE-1 with the nucleoside reverse transcriptase inhibitor (NRTI) stavudine in the context of an acute oxidative stress, reduced DNA damage and mitigated the neurodegeneration of dopaminergic neurons ( Blaudin de Thé et al, 2018 ).…”

Section: Retrotransposons As New Therapeutic Targets In Neurodegenerationmentioning

confidence: 99%

Retrotransposons as a Source of DNA Damage in Neurodegeneration

Peze‐Heidsieck

Bonnifet

Znaidi

et al. 2022

Front. Aging Neurosci.

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The etiology of aging-associated neurodegenerative diseases (NDs), such as Parkinson’s disease (PD) and Alzheimer’s disease (AD), still remains elusive and no curative treatment is available. Age is the major risk factor for PD and AD, but the molecular link between aging and neurodegeneration is not fully understood. Aging is defined by several hallmarks, some of which partially overlap with pathways implicated in NDs. Recent evidence suggests that aging-associated epigenetic alterations can lead to the derepression of the LINE-1 (Long Interspersed Element-1) family of transposable elements (TEs) and that this derepression might have important implications in the pathogenesis of NDs. Almost half of the human DNA is composed of repetitive sequences derived from TEs and TE mobility participated in shaping the mammalian genomes during evolution. Although most TEs are mutated and no longer mobile, more than 100 LINE-1 elements have retained their full coding potential in humans and are thus retrotransposition competent. Uncontrolled activation of TEs has now been reported in various models of neurodegeneration and in diseased human brain tissues. We will discuss in this review the potential contribution of LINE-1 elements in inducing DNA damage and genomic instability, which are emerging pathological features in NDs. TEs might represent an important molecular link between aging and neurodegeneration, and a potential target for urgently needed novel therapeutic disease-modifying interventions.

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“…Antiviral therapy is currently also assessed for treatment of ALS. Antiretroviral combination therapy lowers transcript levels of HERV-K subtype HML-2, an endogenous retrovirus family reported to be derepressed in ALS [ 62 ]. A Phase IIa clinical trial conducted with ALS patients confirmed that antiretroviral therapy (with efficacy against HERV-K HML-2) showed a trend toward delayed disease progression in patients with virological response.…”

Section: Antivirals As Therapeutics To Treat Ndsmentioning

confidence: 99%

Viruses in neurodegenerative diseases: More than just suspects in crimes

Leblanc

Vorberg

2022

PLoS Pathog

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Neurodegenerative diseases (NDs) such as Alzheimer’s and Parkinson’s disease are fatal neurological diseases that can be of idiopathic, genetic, or even infectious origin, as in the case of transmissible spongiform encephalopathies. The etiological factors that lead to neurodegeneration remain unknown but likely involve a combination of aging, genetic risk factors, and environmental stressors. Accumulating evidence hints at an association of viruses with neurodegenerative disorders and suggests that virus-induced neuroinflammation and perturbation of neuronal protein quality control can be involved in the early steps of disease development. In this review, we focus on emerging evidence for a correlation between NDs and viral infection and discuss how viral manipulations of cellular processes can affect the formation and dissemination of disease-associated protein aggregates.

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Inhibition of HERV-K (HML-2) in amyotrophic lateral sclerosis patients on antiretroviral therapy

Cited by 35 publications

References 32 publications

Human endogenous retrovirus-K (HERV-K) reverse transcriptase (RT) structure and biochemistry reveals remarkable similarities to HIV-1 RT and opportunities for HERV-K–specific inhibition

Human endogenous retrovirus-K (HERV-K) reverse transcriptase (RT) structure and biochemistry reveals remarkable similarities to HIV-1 RT and opportunities for HERV-K–specific inhibition

Retrotransposons as a Source of DNA Damage in Neurodegeneration

Viruses in neurodegenerative diseases: More than just suspects in crimes

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