Hepatitis C virus infection of T cells inhibits proliferation and enhances fas-mediated apoptosis by down-regulating the expression of CD44 splicing variant 6.
BACKGROUND
A lymphotropic hepatitis C virus strain (HCV, SB strain, hereafter "SB-HCV") has been shown to infect established T cell lines (Molt-4 and Jurkat) and primary human naive CD4(+) T cells. During T cell development and activation, transient expression of CD44 splicing variant 6 (CD44v6) plays a significant role.


METHODS
SB-HCV was used to infect Molt-4 cells, and their cellular proliferation and CD44 expression was examined.


RESULTS
SB-HCV-infected Molt-4 cells expressed a significantly lower level of the CD44v6 isoform. The infected cells could be divided into 2 carboxyfluorescein succinimidyl ester (CFSE) groups, CFSE-high (indicating low proliferation activity; 34.2% of the cells) and CFSE-low (indicating high proliferation activity; 62.5% of the cells), whereas uninfected cells consisted of only a CFSE-low population. Of the CFSE-high cells, 82.4% were positive for the HCV protein NS5A, whereas only 1.2% of the CFSE-low cells were positive for this protein. Among the HCV proteins, NS5A alone caused the down-regulation of CD44v6 expression. After cells were stimulated with phorbol myristate acetate, the amount of phosphorylated mitogen-activated protein (MAP) kinase was significantly reduced in CFSE-high, SB-HCV-infected Molt-4 cells. After Fas ligand stimulation, SB-HCV-infected Molt-4 cells had increased cleavage of caspase 8 and 3 and enhanced apoptosis, compared with the rates of cleavage and apoptosis in control groups, indicating that SB-HCV infection increased Fas-mediated apoptosis.


CONCLUSIONS
HCV replication in T cells suppresses cellular proliferation and enhances susceptibility to Fas signaling by inhibiting CD44v6 signaling and expression.
Kondo
Yasuteru
Y
Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, USA; Division of Gastroenterology, Tohoku University, Sendai City.
Machida
Keigo
K
Liu
Helene Minyi
HM
Ueno
Yoshiyuki
Y
Kobayashi
Koju
K
Wakita
Takaji
T
Shimosegawa
Tooru
T
Lai
Michael M C
MM
D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D002460:Cell Line; D049109:Cell Proliferation; D015536:Down-Regulation / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D016174:Hepacivirus / Q000502:physiology*; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017361:Viral Nonstructural Proteins / Q000378:metabolism; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase
D048049:Extracellular Signal-Regulated MAP Kinases; D018960:Hyaluronan Receptors; D020929:Mitogen-Activated Protein Kinase Kinases; D020033:Protein Isoforms; D012333:RNA, Messenger; D017361:Viral Nonstructural Proteins; D019014:fas Receptor; D018631:ras Proteins; C497483:CD44 protein, human; C491901:FAS protein, human; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase