Human Endogenous Retroviruses and Their Role in ALS: Avindra Nath, MD

WATCH TIME: 5 minutes

"The same thing that is so important in our survival as humans, and so important in embryogenesis, can also lead to our own demise, ultimately. The laws of nature are very simple, even when we make them complicated."

Human endogenous retroviruses (HERVs) are genomic sequences of retroviral origin that constitute around 8% of the human genome. These HERVs are highly expressed in stem cells but get mostly silenced after cell differentiation. Though most remain dormant, reactivation of HERVs have been implicated in several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Recently, two published papers added evidence to the hypothesis that a reactivation of a specific protein produced by HERV, HERV-K ENV, plays a role in the development of ALS, and that an antibody response against it is protective.^1,2

The studies were published as part of a cooperative research agreement between the National Institute of Neurological Disorders and Stroke (NINDS), and the Switzerland-based biotechnology company GeNeuro Inc. The first of these papers, using mice genetically designed to create HERV-K ENV protein, showed that when adding the cerebrospinal fluid of people with ALS to lab-grown neurons, cells were damaged.¹ When a synthetic antibody designed specifically to recognize HERV-K ENV was added as well to those neurons, the toxic effects were reduced, suggesting that improper activation of the HERV-K ENV gene could be the cause of the symptoms seen in certain cases of sporadic ALS. The second paper showed that higher levels of antibodies against HERV-K ENV were prevalent in patients with ALS, and that these antibody levels were correlated with longer overall survival.²

Avindra Nath, MD, clinical director of the National Institute of Neurological Disorders and Stroke, was a senior author on both of these papers, and decided to sit down and share his insight. In a conversation with NeurologyLive®, Nath provided context on the background of this research, what had been previously observed, and how this further explains certain cases of sporadic ALS.

REFERENCES
1. Steiner JP, Bachani M, Malik N, et al. Human endogenous retrovirus K envelop in spinal fluid of amyotrophic lateral sclerosis. Annals of Neurol. Published July 8, 2022. doi:10.1002/ana.26452
2. Garcia-Montojo M, Simula ER, Fathi S, et al. antibody response to HML-2 may be protective in amyotrophic lateral sclerosis. Annals of Neurol. Published online July 31, 2022. doi:10.1002/ana.26466