Dataset Information

HERV Envelope Proteins: Physiological Role and Pathogenic Potential in Cancer and Autoimmunity.

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.

SUBMITTER: Grandi N

PROVIDER: S-EPMC5861771 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Publications

HERV Envelope Proteins: Physiological Role and Pathogenic Potential in Cancer and Autoimmunity.

Grandi Nicole N Tramontano Enzo E

Frontiers in microbiology 20180314

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 part ...[more]

PMID: 29593697

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Project description:Endogenous retroviruses are the remnants of past retroviral infections that are scattered within mammalian genomes. In humans, most of these elements are old degenerate sequences that have lost their coding properties. The HERV-K(HML2) family is an exception: it recently amplified in the human genome and corresponds to the most active proviruses, with some intact open reading frames and the potential to encode viral particles. Here, using a reconstructed consensus element, we show that HERV-K(HML2) proviruses are able to inhibit Tetherin, a cellular restriction factor that is active against most enveloped viruses and acts by keeping the viral particles attached to the cell surface. More precisely, we identify the Envelope protein (Env) as the viral effector active against Tetherin. Through immunoprecipitation experiments, we show that the recognition of Tetherin is mediated by the surface subunit of Env. Similar to Ebola glycoprotein, HERV-K(HML2) Env does not mediate Tetherin degradation or cell surface removal; therefore, it uses a yet-undescribed mechanism to inactivate Tetherin. We also assessed all natural complete alleles of endogenous HERV-K(HML2) Env described to date for their ability to inhibit Tetherin and found that two of them (out of six) can block Tetherin restriction. However, due to their recent amplification, HERV-K(HML2) elements are extremely polymorphic in the human population, and it is likely that individuals will not all possess the same anti-Tetherin potential. Because of Tetherin's role as a restriction factor capable of inducing innate immune responses, this could have functional consequences for individual responses to infection.Tetherin, a cellular protein initially characterized for its role against HIV-1, has been proven to counteract numerous enveloped viruses. It blocks the release of viral particles from producer cells, keeping them tethered to the cell surface. Several viruses have developed strategies to inhibit Tetherin activity, allowing them to efficiently infect and replicate in their host. Here, we show that human HERV-K(HML2) elements, the remnants of an ancient retroviral infection, possess an anti-Tetherin activity which is mediated by the envelope protein. It is likely that this activity was an important factor that contributed to the recent, human-specific amplification of this family of elements. Also, due to their recent amplification, HERV-K(HML2) elements are highly polymorphic in the human population. Since Tetherin is a mediator of innate immunity, interindividual variations among HERV-K(HML2) Env genes may result in differences in immune responses to infection.

Dataset Information

HERV Envelope Proteins: Physiological Role and Pathogenic Potential in Cancer and Autoimmunity.

Publications

HERV Envelope Proteins: Physiological Role and Pathogenic Potential in Cancer and Autoimmunity.

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