Abstract
Human endogenous retroviruses (HERVs) are relics of ancient infections accounting for about the 8% of our genome. Despite their persistence in human DNA led to the accumulation of mutations, HERVs are still contributing to the human transcriptome, and a growing number of findings suggests that their expression products may have a role in various diseases. Among HERV products, the envelope proteins (Env) are currently highly investigated for their pathogenic properties, which could likely be participating to several disorders with complex etiology, particularly in the contexts of autoimmunity and cancer. In fact, HERV Env proteins have been shown, on the one side, to trigger both innate and adaptive immunity, prompting inflammatory, cytotoxic and apoptotic reactions; and, on the other side, to prevent the immune response activation, presenting immunosuppressive properties and acting as immune downregulators. In addition, HERV Env proteins have been shown to induce abnormal cell-cell fusion, possibly contributing to tumor development and metastasizing processes. Remarkably, even highly defective HERV env genes and alternative env splicing variants can provide further mechanisms of pathogenesis. A well-known example is the HERV-K(HML2) env gene that, depending on the presence or the absence of a 292-bp deletion, can originate two proteins of different length (Np9 and Rec) proposed to have oncogenic properties. The understanding of their involvement in complex pathological disorders made HERV Env proteins potential targets for therapeutic interventions. Of note, a monoclonal antibody directed against a HERV-W Env is currently under clinical trial as therapeutic approach for multiple sclerosis, representing the first HERV-based treatment. The present review will focus on the current knowledge of the HERV Env expression, summarizing its role in human physiology and its possible pathogenic effects in various cancer and autoimmune disorders. It moreover analyzes HERV Env possible exploitation for the development of innovative therapeutic strategies.
Highlights
Human endogenous retroviruses (HERVs) are transposable elements acquired along primate evolution through multiple infections extinct exogenous retroviruses
An important issue to be addresses is if the specificity of expression from a given locus can be associated with a defined molecular mechanism of pathogenesis
Our understanding of HERVs has grown in the last three decades and, it is evident that their expression is a normal phenomenon and, cannot be used as the only evidence of their involvement in human disorders
Summary
Human endogenous retroviruses (HERVs) are transposable elements acquired along primate evolution through multiple infections extinct exogenous retroviruses. The loss of this portion characterizes type I HML2 sequences, in which an alternative splice donor site upstream of the deletion generates the np mRNA (Figure 1B) As described below, both Rec and Np9 have been intensively studied for their possible role in human health. According to the most updated and comprehensive analysis, performed with the software RetroTector (Sperber et al, 2007), HERVs can be classified in 39 “canonical” groups and 31 “noncanonical” clades characterized by several degrees of mosaicism (Vargiu et al, 2016) (Table 1) This classification is based on a multi-step approach and provided a remarkable background for the characterization of single HERV groups, revealing insights on FIGURE 1 | General structure of HERV DNA sequences. From other HERV groups, the HERV-K(HML2) env gene presents alternative splicing sites, leading to the presence of a full length transcript with structural significance plus two types of accessory variants, named rec and np, that subdivide the HML2 sequences into two types. Type I HML2 elements present a characteristic 292-bp env deletion, leading to the use of an upstream splice donor and the subsequent production of a shorter protein, named Np9; while type II HML2 sequences retained such portion and use the downstream splice donor site to encode for a longer protein, named Rec
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