CD59 incorporation protects hepatitis C virus against complement-mediated destruction

Abstract

Several enveloped viruses including HIV-1, CMV, HSV-1, Ebola virus, vaccinia virus, and influenza virus have been found to incorporate host regulators of complement activation (RCA) into their viral envelopes and, as a result, escape antibody-dependent complement-mediated lysis (ADCML). HCV is an enveloped virus of the family Flaviviridae and incorporates more than 10 host lipoproteins. Patients chronically infected with HCV develop high-titer and cross-reactive neutralizing antibodies (nAbs) yet fail to clear the virus, raising the possibility that HCV may also use the similar strategy of RCA incorporation to escape ADCML. The current study was therefore undertaken to determine whether HCV virions incorporate biologically functional CD59, a key member of RCA. Our experiments provided several lines of evidence demonstrating that CD59 was associated with the external membrane of HCV particles derived from either Huh7.5.1 cells or plasma samples from HCV-infected patients. First, HCV particles were captured by CD59-specific Abs. Second, CD59 was detected in purified HCV particles by immunoblot analysis and in the cell-free supernatant from HCV-infected Huh7.5.1 cells, but not from uninfected or Ad5 (a nonenveloped cytolytic virus)-infected Huh7.5.1 cells by ELISA. Last, abrogation of CD59 function with its blockers increased the sensitivity of HCV virions to ADCML, resulting in a significant reduction of HCV infectivity. Additionally, direct addition of CD59 blockers into plasma samples from HCV-infected patients increased autologous virolysis. Conclusion our study, for the first time, demonstrates that CD59 is incorporated into both cell line-derived and plasma primary HCV virions at levels that protect against ADCML. This is also the first report to show that direct addition of RCA blockers into plasma from HCV-infected patients renders endogenous plasma virions sensitive to ADCML.

NF-κB and Enhancer-binding CREB Protein Scaffolded by CREB-binding Protein (CBP)/p300 Proteins Regulate CD59 Protein Expression to Protect Cells from Complement Attack

“…In contrast, the acquired overexpression of CD59 confers resistance to complement-mediated cytolysis in cells infected with hepatitis B virus (9), hepatitis C virus (34), and human immunodeficiency virus (35), contributing to the occurrence of persistent infections. Furthermore, chronic inflammation, especially when induced by pathogens, has been implicated in tumorigenesis, where many proinflammatory and pathogenic virulence factors are produced in local tumor sites (36).…”

Hepatitis C Virus Infection Upregulates CD55 Expression on the Hepatocyte Surface and Promotes Association with Virus Particles

“…HCV incorporates CD59 into the viral lipid bilayer at biologically functional levels (17) and protects against antibody-dependent complement-mediated lysis. Thus, it is difficult to examine the role of CD55 in maintaining cell viability related to complement attack by depleting it alone in cells supporting HCV growth.…”

“…Recent studies have suggested that incorporation of the complement-regulatory protein CD59 in HCV in plasma as well as proteins derived from cell lines (17) protected HCV from antibody-dependent complement-mediated lysis. Analogously, HBV X protein has been implicated in increasing expression of CD59 in hepatoma cell lines.…”

Hepatitis C Virus Suppresses C9 Complement Synthesis and Impairs Membrane Attack Complex Function

“…The ER also plays a critical part in the synthesis and modification of glycosylphosphatidylinositol-anchored proteins (GPI-Aps) such as CD55 and CD59 in eukaryotic cells. Thus, it is possible for HCV to encounter and obtain CD55 or CD59 in the ER and other cellular organelles (23). Therefore, working with a susceptible model was necessary to determine the qualitative nature of the complement in chronically HCV-infected patient sera.…”