Virus receptor trap neutralizes coxsackievirus in experimental murine viral myocarditis.
OBJECTIVE
The coxsackie and adenovirus receptor (CAR) and the decay-accelerating factor (DAF) are receptors for coxsackievirus B3 (CVB3), which is known as the major cause of human viral myocarditis. We investigated the potential for therapeutic use of soluble virus receptor fusion proteins.


METHODS
We designed and generated a novel virus receptor trap (hCAR-hDAF:Fc) consisting of both CVB3 receptors and the Fc portion of human IgG1 and evaluated its antiviral effects in experimental CVB3 myocarditis.


RESULTS
Among four soluble virus receptor fusion proteins (hCAR:Fc, hDAF:Fc, hCAR-hDAF:Fc and hDAF-hCAR:Fc), hCAR:Fc and hCAR-hDAF:Fc in the supernatant of transfected cells neutralized echovirus, adenovirus, and various serotypes of CVB in a dose-dependent manner. Both soluble viral receptor proteins bound to the VP0 and VP1 capsid proteins of CVB3. The in vivo efficacy of viral receptor proteins was evaluated by intramuscular injection of plasmid (hCAR:Fc or hCAR-hDAF:Fc) followed by electroporation in a murine model of CVB3 myocarditis. Serum levels of the virus receptor proteins increased relative to baseline values from day 3 and peaked on day 14 at 12.9-fold for hCAR:Fc and 7.1-fold for hCAR-hDAF:Fc. The 3-week survival rate was significantly higher in hCAR-hDAF:Fc-treated mice (61%) than in hCAR:Fc-treated mice (29%) and in controls (15%; p<0.05). Myocardial inflammation, fibrosis, and myocardial virus titers were all significantly reduced in the hCAR:Fc and hCAR-hDAF:Fc groups compared to the controls.


CONCLUSIONS
Our soluble virus receptor trap, hCAR-hDAF:Fc, attenuated viral infection, myocardial inflammation, and fibrosis, resulting in higher survival rates in mice with coxsackieviral myocarditis. Furthermore, it consists exclusively of human components, and we demonstrated that this soluble virus receptor trap may be used as a potential candidate for a novel therapeutic agent for the treatment of acute viral myocarditis during the viremic phase.
Lim
Byung-Kwan
BK
Department of Medicine, Sungkyunkwan University School of Medicine, Cardiac and Vascular Center, Samsung Medical Center, 50 Il-won Dong, Kangnam-Ku, Seoul 135-710, Korea.
Choi
Jin-Ho
JH
Nam
Jae-Hwan
JH
Gil
Chae-Ok
CO
Shin
Jae-Ok
JO
Yun
Soo-Hyeon
SH
Kim
Duk-Kyung
DK
Jeon
Eun-Seok
ES
D000208:Acute Disease; D000818:Animals; D036022:Capsid Proteins / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D003384:Coxsackievirus Infections / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D004195:Disease Models, Animal; D018274:Electroporation / Q000379:methods; D015316:Genetic Therapy / Q000379:methods*; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009205:Myocarditis / Q000378:metabolism / Q000473:pathology / Q000628:therapy* / Q000821:virology; D011991:Receptors, Virus / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D016019:Survival Analysis
D036022:Capsid Proteins; D015815:Cell Adhesion Molecules; C106607:FCGBP protein, human; D008565:Membrane Proteins; D011991:Receptors, Virus; D011993:Recombinant Fusion Proteins; C105941:coxsackievirus B receptor