TY - JOUR
T1 - Hepatitis C virus infection of T cells inhibits proliferation and enhances Fas-mediated apoptosis by down-regulating the expression of CD44 splicing variant 6
AU - Kondo, Yasuteru
AU - Machida, Keigo
AU - Liu, Helene Minyi
AU - Ueno, Yoshiyuki
AU - Kobayashi, Koju
AU - Wakita, Takaji
AU - Shimosegawa, Tooru
AU - Lai, Michael M.C.
N1 - Funding Information:
Received 2 July 2008; accepted 23 September 2008; electronically published 21 January 2009. Potential conflicts of interest: none reported. Financial support: National Institutes of Health (research grants AI40038 to M.M.C.L. and CA108302 to M.M.C.L.). Reprints or correspondence: Michael M. C. Lai, 2011 Zonal Ave. HMR500, Los Angeles, CA 90033 (michlai@usc.edu).
PY - 2009/3/1
Y1 - 2009/3/1
N2 - 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. Conclusion. HCV replication in T cells suppresses cellular proliferation and enhances susceptibility to Fas signaling by inhibiting CD44v6 signaling and expression.
AB - 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. Conclusion. HCV replication in T cells suppresses cellular proliferation and enhances susceptibility to Fas signaling by inhibiting CD44v6 signaling and expression.
UR - http://www.scopus.com/inward/record.url?scp=61849126758&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=61849126758&partnerID=8YFLogxK
U2 - 10.1086/596739
DO - 10.1086/596739
M3 - Article
C2 - 19199548
AN - SCOPUS:61849126758
VL - 199
SP - 726
EP - 736
JO - Journal of Infectious Diseases
JF - Journal of Infectious Diseases
SN - 0022-1899
IS - 5
ER -