A human mutant CD4 molecule resistant to HIV-1 binding restores helper T-lymphocyte functions in murine CD4-deficient mice

被引：0

作者：

Kim D.-K. ^{[1
]}

Satoko T.-H. ^{[2
]}

Shinohara N. ^{[3
]}

Nakauchi H. ^{[4
]}

机构：

[1] Cell and Gene Therapy Research Institute, Pochon CHA University, CHA General Hospital

[2] Department of Immunology, Institute of Basic Medical Sciences, University of Tsukuba, Ibaraki

[3] Department of Obstetrics and Gynecology, Kitasato University School of Medicine, Sagamihara

[4] Laboratory of Stem Cell Therapy, Institute of Medical Science, University of Tokyo

来源：

Experimental & Molecular Medicine | 2007年 / 39卷 / 1期

关键词：

Antigens; CD4; Aquired immunodefiency syndrome; CD4-positive T-lymphocytes; HIV-1; Mice; transgenic; T-lymphocytes; helper-inducer;

D O I：

10.1038/emm.2007.1

中图分类号：

学科分类号：

摘要：

CD4 is a cell surface glycoprotein that acts as a co-receptor for the T cell antigen receptor by binding to a non-polymorphic portion of MHC molecules. CD4 also functions as a receptor for human immunodeficiency virus type-I (HIV-1) because the viral envelope glycoprotein gp120 binds to CD4 with a high affinity. We have previously demonstrated that introduction of mutations into CD4 abolished the binding of gp120 and prevented HIV-1 from entering cells and spreading. However, whether introduction of such mutations into CD4 causes decreased binding to MHC and loss of function is yet to be determined. We generated transgenic mouse lines by injecting a mutant human CD4 (muthCD4) gene under a murine CD4 enhancer/promoter to ensure tissue and stage specific expression. To exclude the influence of endogenous murine CD4, transgenic mice were crossed with murine CD4-targeted mice to produce muthCD4 transgenic mice lacking endogenous CD4 (muthCD4TG/KO mice). In these mice, T lymphocytes expressing muthCD4 expanded and matured in the thymus and were present in the spleen and lymph nodes. They also activated B cells to mount an antibody response to a T-dependent antigen. The results from this study suggest that a human variant of CD4 modified to be resistant to HIV-1 binding can rescue the signaling for T cell development in the thymus in vivo, having helper T cell functions. Thus, further characterization of muthCD4 molecules should open the way to new HIV treatment modalities.

引用

页码：1 / 7

页数：6

共 23 条

[1] Biddison W.E., Rao P.E., Talle M.M., Goldstein G., Shaw S., Possible involvement of the OKT4 molecule in T cell recognition of class II HLA antigen, J Exp Med, 156, pp. 1065-1076, (1982)
[2] Clayton L.K., Sieh M., Pious D.A., Reinherz E.L., Identification of human CD4 residues affecting class II MHC versus HIV-1 gp120 binding, Nature, 339, pp. 548-551, (1989)
[3] Coffin J.M., HIV population dynamics in vivo: Implication for genetic variation, pathogenesis, and therapy, Science, 267, pp. 483-489, (1995)
[4] Fleury S., Lamarre D., Meloche S., Ryu S.E., Cantin C., Hendrickson W.A., Sekaly R.P., Mutational analysis of the interaction between CD4 and class II MHC: Class II antigens contact CD4 on a surface opposite the gp120-binding site, Cell, 66, pp. 1037-1049, (1991)
[5] Killeen N., Sawada S., Littman D.R., Regulated expression of human CD4 rescues helper T cell development in mice lacking expression of endogenous CD4, EMBO, 12, pp. 1547-1553, (1993)
[6] Krensky A.M., Reiss C.S., Mier J.W., Strominger J.L., Burakoff S.J., Long-term human cytolytic T-cell lines allospecific for HLA-DR6 antigen are OKT4 <sup>+</sup> , Proc Natl Acad Sci USA, 79, pp. 2365-2369, (1982)
[7] Kunkel T.A., Rapid and efficient site specific mutagenesis without phenotypic selection, Proc Natl Acad Sci USA, 82, pp. 488-492, (1985)
[8] Lamarre D., Ashikenazi A., Fleury S., Smith D.H., Sekaly R.P., Capon D.J., The MHC-binding and gp120-binding functions of CD4 are separable, Science, 245, pp. 743-746, (1989)
[9] Lamarre D., Capon D.J., Karp D.R., Gregory T., Long E.O., Sekaly R.P., Class II MHC molecules and the HIV gp120 envelop protein interact with functionally distinct regions of the CD4 molecule, EMBO J, 8, pp. 3271-3277, (1989)
[10] Landau N.R., Warton M., Littman D.R., The envelope glycoprotein of the human immunodeficiency virus binds to the immunoglobulin-like domain of CD4, Nature, 334, pp. 159-162, (1988)

← 1 2 3 →