MSRV envelope protein is a potent, endogenous and pathogenic agonist of human toll-like receptor 4: Relevance of GNbAC1 in multiple sclerosis treatment

Abstract

Multiple sclerosis associated retrovirus envelope protein (MSRV-Env) was repeatedly detected in brain lesions and blood of multiple sclerosis (MS) patients. We performed the first pharmacological characterisation of MSRV-Env on recombinant and native human TLR4. MSRV-Env is a full and highly potent TLR4 agonist of endogenous origin. MSRV-Env induces TLR4-dependent pro-inflammatory stimulation of immune cells in vitro and in vivo, and impairs oligodendrocytes precursor cells differentiation to myelinating oligodendrocytes. MSRV-Env may play a role in chronic inflammation and impaired remyelination in MS. GNbAC1, a selective monoclonal antibody, antagonizes MSRV-Env pathogenic effects and represents an innovative therapeutic approach of MS.

An ancestral retroviral protein identified as a therapeutic target in type-1 diabetes

“…HERV-W-Env was shown to promote monocyte maturation, DC differentiation, and release of proinflammatory cytokines, such as TNFα, IL1β, IL12β, and IL6 (34)(35)(36). In this respect, we have shown that HERV-W-Env affects the innate immune system of T1D patients, as the presence of this protein correlates with CD68 + cell detection in the exocrine pancreas ( Figure 3C).…”

“…This inhibition reached 50% at 100 ng/ml of HERV-W-Env in human β cells, without affecting cell viability ( Figure 5D). The underlying mechanism of this inhibition requires further investigations, though it has already been described that HERV-W-Env exerts its pathogenic effects through an interaction with the TLR4 receptor (35,36). From a T1D perspective, this mechanism appears relevant, as TLR4 is expressed by β cells (42)(43)(44).…”

“…Proinflammatory and autoimmune properties of HERV-W-Env have been characterized in vivo and in vitro (23,(34)(35)(36)(37) and appeared to be mediated by the interaction with TLR4, a receptor involved in the initiation of innate immune response against microbial infection (35). The consistent results of preclinical studies have led to the development of a monoclonal antibody targeting HERV-WEnv, named GNbAC1, which is currently tested in clinical trials for an MS indication (38).…”

Клінічна Характеристика Нового Сироваткового Біомаркера Як Потенційного Продукту Розпаду Білка Ендогенного Ретровірусу Людини У Хворих На розсіяний Склероз

“…Беручи до уваги, що на даний момент ендогенні ре-тровіруси досліджуються як етіологічний, а також пато-генетичний фактор РС, розроблено експериментальні засоби хворобо-модифікуючої терапії (ХМТ), мішенню яких є певні компоненти цих вірусів [17,18]. У даний час продовжуються два міжнародні рандомізовані клі-нічні дослідження з оцінки ефективності застосування моноклональних антитіл проти РСАРВ у хворих на РС [17,19].…”

“…У даний час продовжуються два міжнародні рандомізовані клі-нічні дослідження з оцінки ефективності застосування моноклональних антитіл проти РСАРВ у хворих на РС [17,19].…”