Human Endogenous Retroviruses as Novel Therapeutic Targets in Neurodegenerative Disorders

Abstract

Human Endogenous Retroviruses comprise approximately 8% of the human genome, serving as fragments of ancient retroviral infections. Although they are generally maintained in a silenced state by robust epigenetic mechanisms, specific HERV groups, particularly HERV-W and HERV-K, can become derepressed under specific pathological conditions, thereby contributing to the initiation and progression of neuroinflammatory and neurodegenerative processes. Preclinical studies and clinical trials, such as those investigating monoclonal antibodies, indicate that directly targeting these elements may offer a novel therapeutic strategy. In this review, we provide an overview of HERVs' biology, examine their role in neurodegenerative diseases such as amyotrophic lateral sclerosis, multiple sclerosis, Alzheimer's disease, and Parkinson's disease, and explore their therapeutic prospects, highlighting both the challenges and the potential future research directions needed to translate these approaches into clinical interventions.

Keywords: Alzheimer′s disease; HERVs; Parkinson′s disease; amyotrophic lateral sclerosis; epigenetics; monoclonal antibodies; multiple sclerosis; neurodegeneration; vaccines.

Figure 2

Regional distribution of HERV RNA transcripts in the human brain. Quantification of HERV RNA expression across distinct anatomical regions of the human brain. The cerebellar hemisphere and cerebellum exhibit the highest abundance of HERV RNAs (1284 and 1193 transcripts, respectively), followed by the pituitary gland (221 transcripts) and basal ganglia (79 transcripts). Lower levels are observed in cortical and limbic regions, including the frontal cortex (57), cerebral cortex (44), hypothalamus (15), anterior cingulate cortex (8), and hippocampus (7) [76].

Figure 1

Schematic representation of the HERV proviral genome structure. The figure illustrates the organization of a typical human endogenous retrovirus (HERV) provirus, including the 5′ and 3′ long terminal repeats (LTRs), which are composed of the U3, R, and U5 regions. The internal coding regions are shown in sequential order: gag (encoding MA, CA, and NC), pro (encoding the viral protease, PR), pol (encoding reverse transcriptase, RT, RNase H, RH, and integrase, IN), and env (encoding the surface, SU, and transmembrane, TM, subunits of the envelope protein). Also indicated are the primer binding site, PBS, and the polypurine tract, PPT, which play critical roles in the initiation of reverse transcription and second-strand DNA synthesis, respectively.