Anti-CD81 antibodies can prevent a hepatitis C virus infection in vivo

Abstract

The viral life cycle of the hepatitis C virus (HCV) has been studied mainly using different in vitro cell culture models. Studies using pseudoviral particles (HCVpp) and more recently cell culture-derived virus (HCVcc) suggest that at least three host cell molecules are important for HCV entry in vitro: the tetraspanin CD81, the scavenger receptor class B member I, and the tight junction protein Claudin-1. Whether these receptors are equally important for an in vivo infection remains to be demonstrated. We show that CD81 is indispensable for an authentic in vivo HCV infection. Prophylactic treatment with anti-CD81 antibodies completely protected human liver-uPA-SCID mice from a subsequent challenge with HCV consensus strains of different genotypes. Administration of anti-CD81 antibodies after viral challenge had no effect. M ore than 170 million people worldwide are infected with the hepatitis C virus (HCV). The lack of an effective HCV vaccine and the high cost and considerable side effects of the current standard therapies have a major impact on global public health. HCV is now a leading cause of liver cirrhosis, hepatocellular carcinoma, and liver transplantation. 1 The precise mechanism by which HCV attaches to and enters host cells remains unclear. Pileri et al. 2 identified the tetraspanin CD81 (TAPA-1) as a putative receptor for HCV. This 21-kDa surface molecule, composed of four transmembrane and two extracellular domains, efficiently bound recombinantly produced E2, one of the two viral envelope proteins. Experiments using pseudoviral particles (HCVpp) containing the HCV envelope proteins [3][4][5][6] or the recently developed infectious HCV cell culture system 7-11 have shown that CD81 expression on the target cell is essential for HCV infection of transformed hepatocytes in vitro.Despite the evidence provided by numerous in vitro experiments, definitive proof of the role of CD81 in HCV infection in vivo is missing. It is well known that cell lines are not necessarily representative for the tissue or organ of origin. Moreover, other molecules, such as scavenger receptor class B member I, 12,13 C-type lectins L-SIGN and DC-SIGN, 14-17 low-density lipoprotein receptor, 18,19 glycosaminoglycans, 20,21 and more recently, Claudin-1 22 and lipoprotein lipase, 23 have been identified as putative HCV receptors or coreceptors. In addition, all these experiments have been performed using HCVpp or cellculture-derived virus (HCVcc), which have different characteristics compared with natural HCV particles. 24 More recently, Molina et al. 25 reported that infection of primary hepatocyte cultures with serum-derived HCV could be inhibited by using anti-CD81 antibodies or via transduction of small interfering RNA that inhibited CD81 membrane expression.We therefore investigated whether HCV infection could be prevented in vivo by administering anti-CD81 mAbs to human liver-uPA-SCID mice. uPA-SCID mice are immunodeficient mice that suffer from a severe, transgene-induced liver disease. 26 These animals can be successful...

Cellular models for the screening and development of anti-hepatitis C virus agents

“…Interestingly, a soluble form of E2 has been suggested to link both CD81 and SR-BI (Heo et al, 2006). A recent work confirms these finding at the in vivo level (Meuleman et al, 2008).…”

Trachelogenin, a novel inhibitor of hepatitis C virus entry through CD81

“…Of the identified entry factors, only CD81 and SRB1 have been reported to interact directly with the soluble form of HCV envelope glycoprotein E2, which is a key viral protein throughout the life cycle and disease progression of HCV infections (Qin et al, 2015;Vieyres et al, 2010). Specific anti-CD81 mAbs effectively interfere with E2-CD81 interactions and inhibit HCV infections in humanized mice (Ji et al, 2015;Meuleman et al, 2008). However, as CD81 is a ubiquitously expressed protein in almost all tissues, the toxicity issues limit its use.…”

Interferon-Free Strategies without a Nucleoside/Nucleotide Analogue

“…Monoclonal antibodies directed against viral entry factors (e.g., CD81-mAbs, anti-SR-BI mAbs, ITX5061), or EGFR kinase (erlotinib) and the cholesterol absorption NPC1L1 inhibitor ezetimibe have been shown to protect or delay HCV infection in mice. [65][66][67][68][69][70] As of today, development of these compounds (except ITX5061) is yet in preclinical stages. In a recent phase 1b study ITX5061, however, did not meet protocol-defined criteria for viral suppression.…”