Human Endogenous Retroviruses in Neurological Diseases

Abstract

The causes of multiple sclerosis and amyotrophic lateral sclerosis have long remained elusive. A new category of pathogenic components, normally dormant within human genomes, has been identified: human endogenous retroviruses (HERVs). These represent ∼8% of the human genome, and environmental factors have reproducibly been shown to trigger their expression. The resulting production of envelope (Env) proteins from HERV-W and HERV-K appears to engage pathophysiological pathways leading to the pathognomonic features of MS and ALS, respectively. Pathogenic HERV elements may thus provide a missing link in understanding these complex diseases. Moreover, their neutralization may represent a promising strategy to establish novel and more powerful therapeutic approaches.

Figure 1

Relative Proportions of Different Types of DNA Sequences within the Human Genome, and the Prototypic DNA Sequence of Complete Human Endogenous Retrovirus (HERV) Genomes. (A) DNA sequences representing remnants of mobile genetic machinery represent nearly 50% of the human genome. These are predominantly retrotransposons, that use RNA intermediates and a ‘copy-paste’ mechanism for retrointegration into chromosomes, and DNA transposons that use a ‘cut and paste’ mechanism; these represent 42% and 3% of the human genome, respectively . Among retrotransposons, an important group is represented by the endogenous retroviruses (ERVs; HERVs for human ERVs) that entered the genome of species through infections of germline cells during evolution leading to subsequent endogenization – integration into the genome and presence in the DNA of every cell of the offspring . About 8% of the human genome is constituted by HERV sequences; complete sequencing has revealed that intact coding sequences for functional HERV proteins represent <3%, if not 1% , . The remaining sequences comprise non-coding DNA, often within introns of ‘classical’ genes, with a potential role in generating non-coding RNAs . (B) Endogenous HERV DNA sequences are often truncated, and contain mutations, insertions, or deletions, but complete copies are also present. The gag (group-specific antigen), pol (polymerase), and env (envelope) genes encode structural proteins and are flanked by two inverted repeats of non-coding regions comprising many regulatory functions (promoter, enhancer, primer-binding site for reverse transcription, and others). Abbreviation: LTR, long terminal repeat.

Figure 2

Successive Steps Leading to Endogenization of Retroviruses and to Multicopy Endogenous Retroviral (ERV) Families in Descendants. This illustration depicts the successive steps of retroviral endogenization, starting from infection of gametes, integration of a DNA retroviral copy (provirus) into a chromosome, giving birth to a viable individual inheriting and retaining this copy in the DNA of all cells and transmitting this to its offspring. Throughout successive generations and evolution, both endogenous retrotranspositions and reinfections of the germline of particular individuals (provided that the exogenous strain persists in the environment) generates multiple and variable copy numbers in the final population. This variability has been well known in some animal species and has recently also been evidenced in humans . Abbreviations: env, envelope; gag, group-specific antigen; LTR, long terminal repeat; pol, polymerase.

Figure 3

Hypothesized Human Endogenous Retrovirus (HERV)-Mediated Activation Cascades Leading to the Pathogenesis of Multiple Sclerosis (MS). This illustration depicts a hypothetical pathogenic pathway for MS involving HERV-W activation and envelope (Env) protein expression triggered by an environmental factor. This causes dysregulated inflammatory and immune responses accompanied by activation of microglial cells, which thereby also express pathogenic HERV-W Env protein (formerly called MSRV-Env). The proposed direct cytotoxic effect on endothelial cells through TLR4 activation could contribute to T cell homing through upregulated ICAM-1 expression in response to cytokines and chemokines secreted from the initial site of HERV-W expression.

Figure 4

Normal Differentiation of Oligodendrocyte Precursor Cells (OPCs) versus Inhibition of Oligodendroglial Maturation by Human Endogenous Retrovirus HERV-W Envelope (Env) Protein. Activation of Toll-like Receptor 4 (TLR4) on OPCs by the pathogenic HERV-W Env protein blocks the differentiation of these cells, with potential impact on naturally occurring myelin repair. OPCs are targeted by pHERV-W Env either through contacts with microglia that present pHERV-W Env protein at the cell membrane surface, or through interaction with secreted or shed pHERV-W Env protein in the extracellular space.

Figure 5

Hypothetical Scenario Involving Human Endogenous Retrovirus HERV-K Activation Leading to Amyotrophic Lateral Sclerosis (ALS). This scenario depicts the hypothesized origin of retroviral endogenizations during the evolution of species millions of years ago, and the transmission of HERV copies to humans in which HERV-K copies may remain dormant (latent) or activated by still unknown mechanisms. This figure relates to the most recent HERV-K insertions (and not to previous HERV-K/HML-2 insertions at ∼30 million years ago), which are thought to be the most active copies because they are normally less mutated than earlier insertions. When activated in specific areas of the central nervous system, the resulting pathogenic pathway involves HERV-K expression and release of its envelope (Env) protein that causes neurotoxicity in targeted motor neurons.

Figure 6

Proposed Global Model: From Gene–Environment Interactions to a Targeted Therapy in Multiple Sclerosis (MS). The proposed model presents how, after being activated by variable and multiple environmental factors, HERV-W (formerly named MSRV) expresses a pathogenic envelope (Env) protein that appears to represent an unique agonist in the pathway. (i) Downstream HERV-W DNA expression and (ii) upstream pathogenic pathways that are activated in multiple direct and indirect target cells. An antibody neutralizing this pathogenic protein might block the pathogenic pathway at this level, independently of multiple environmental triggers and pathogenic downstream cascades, without interfering with host physiological functions. Abbreviations: EBV, Epstein–Barr virus; HHV-6, human herpes virus 6; HSV-1, herpes simplex virus 1; OPC, oligodendroglial precursor cell; VZV, varicella-zoster virus.