The Expression of the Hepatocyte SLAMF3 (CD229) Receptor Enhances the Hepatitis C Virus Infection

Abstract

Hepatitis C virus (HCV) is a leading cause of cirrhosis and liver cancer worldwide. We recently characterized for the first time the expression of Signaling Lymphocyte Activating Molecule 3 (SLAMF3) in human hepatocytes and here, we report that SLAMF3 interacts with the HCV viral protein E2 and is implicated in HCV entry process. We found a strong correlation between SLAMF3 expression level and hepatocyte susceptibility to HCV infection. The use of specific siRNAs to down-modulate SLAMF3 expression and SLAMF3-blocking antibodies both decreased the hepatocytes susceptibility to HCV infection. Moreover, SLAMF3 over-expression significantly increased susceptibility to HCV infection. Interestingly, experiments with peptides derived from each SLAMF3 domain showed that the first N-terminal extracellular domain is essential for interaction with HCV particles. Finally, we showed that recombinant HCV envelop protein E2 can bind SLAMF3 and that anti-SLAMF3 antibodies inhibited specifically this interaction. Overall, our results revealed that SLAMF3 plays a role during HCV entry, likely by enhancing entry of viral particle within hepatocytes.

SLAM Family Receptor Signaling in Viral Infections: HIV and Beyond

“…More specifically, they noted that the HCV envelope protein, E2, was responsible for this interaction. In further support of this important interaction for HCV pathogenesis, it was observed that SLAMF3 expression on hepatocytes correlated with their susceptibility to HCV infection [42].…”

“…Measles [39] Th2 polarization [17,40] T cells, B cells, macrophages, DCs, platelets, HSCs SLAMF2 (CD48) Down-regulated via CMV viral protein m154 [41] Regulates DC survival and antigen-presentation during T cell interactions [31] Nearly all hematopoietic cells SLAMF3 (Ly-9, CD229) HCV E2 protein [42] CD4 + T cells, CD8 + T cells, B cells, plasma cells, NK cells, NKT cells, ILCs, DCs, monocytes, macrophages, and HSCs…”

“…The third member of the SLAM family of receptors, SLAMF3, is widely expressed on lymphocytes, notably on CD4 + T cells, CD8 + T cells, B cells, plasma cells, NK cells, NKT cells, innate lymphoid cells (ILCs), DCs, monocytes, macrophages, and hematopoietic stem cells (HSCs). Interestingly, it is also known to be expressed on hepatocytes [42]. SLAMF3 is a relatively understudied member of the SLAM family, and to date, studies have only revealed roles for SLAMF3 in control of T cell inflammatory responses and NKT cell development [5].…”

“…SLAMF3's expression on hepatocytes is its only known direct link to viral infections. A single report has shown that HCV is able to bind directly to the first N-terminal domain of SLAMF3 and use this as a cellular entry mechanism [42]. More specifically, they noted that the HCV envelope protein, E2, was responsible for this interaction.…”

Viral CD229 (Ly9) homologs as new manipulators of host immunity

“…52,53 In line with this, CD229 has been proposed to serve as an entry receptor for hepatitis C virus on human hepatocytes through the interaction with the virion E2 glycoprotein. 54 However, this finding remains controversial and further investigations will be required to support them.…”