Kitagawa M, Aizawa S, Kamisaku H, Ikeda H, Hirokawa K, Sado T
Department of Pathology, Faculty of Medicine, Tokyo Medical and Dental University, Japan.
Blood. 1995 Aug 15;86(4):1557-63.
Fv-4 is a mouse gene that dominantly confers resistance to infection by ecotropic murine leukemia virus (MuLV). We previously demonstrated that mixed radiation bone marrow chimeras containing Fv-4r-bearing BALB/c-Fv-4Wr (C4W) bone marrow and Fv-4r-bearing C3H/He (C3H) bone marrow grafted into C3H recipient mice (C4W+C3H-->C3H) were resistant to Friend leukemia virus (FLV)-induced leukemogenesis, even when they contained as high as 70% C3H-derived cells. This indicates that FLV-sensitive C3H-derived cells are rendered refractory to infection and/or transformation with FLV when they coexist in mice with Fv-4r-bearing cells. To investigate the mechanism of Fv-4 resistance to FLV-induced leukemogenesis, we first examined the expression of Fv-4r env antigen in the peripheral blood mononuclear cells (PBMC) of these chimeras. The Fv-4r env antigen was present not only on C4W-derived cells, but also on Fv-4r-bearing C3H-derived cells in C4W+C3H-->C3H mixed bone marrow chimeras. The Fv-4r env antigen that binds to the cells surface of C3H cells was found in sera from normal C4W mice, C4W-->C3H chimeras, and C4W+C3H-->C3H mixed chimeras. The serum Fv-4r env antigen binds to ecotropic MuLV receptors, shown by specific binding to transfectant mink cells expressing ecotropic MuLV receptor, but not to parental mink cells. To determine whether the binding of Fv-4r env antigen to the putative MuLV receptors would block FLV infection, C3H thymocytes or spleen cells that had been preincubated with C4W serum were mixed with FLV and the subsequent production of MuLV specific antigens was examined. C3H thymocytes or spleen cells treated with C4W serum became refractory to binding by FLV. These results provide evidence that the Fv-4r env antigen is released from C4W-derived cells in vivo and binds to cells expressing surface receptors for ecotropic MuLV, thereby protecting them from infection with FLV. The implication of these findings for gene therapy of retrovirus-induced disease such as acquired immune deficiency syndrome (AIDS) is discussed.
Fv - 4是一种小鼠基因，它能显性赋予对亲嗜性鼠白血病病毒（MuLV）感染的抗性。我们先前证明，将含有携带Fv - 4r的BALB/c - Fv - 4Wr（C4W）骨髓和携带Fv - 4r的C3H/He（C3H）骨髓的混合辐射骨髓嵌合体移植到C3H受体小鼠（C4W + C3H→C3H）中，即使它们含有高达70%的C3H来源细胞，也对Friend白血病病毒（FLV）诱导的白血病发生具有抗性。这表明，当FLV敏感的C3H来源细胞与携带Fv - 4r的细胞共存于小鼠中时，它们对FLV的感染和/或转化变得具有抗性。为了研究Fv - 4对FLV诱导白血病发生的抗性机制，我们首先检测了这些嵌合体外周血单核细胞（PBMC）中Fv - 4r env抗原的表达。Fv - 4r env抗原不仅存在于C4W来源的细胞上，也存在于C4W + C3H→C3H混合骨髓嵌合体中携带Fv - 4r的C3H来源细胞上。在正常C4W小鼠、C4W→C3H嵌合体和C4W + C3H→C3H混合嵌合体的血清中发现了与C3H细胞表面结合的Fv - 4r env抗原。血清Fv - 4r env抗原与亲嗜性MuLV受体结合，这通过与表达亲嗜性MuLV受体的转染貂细胞特异性结合得以证明，但与亲代貂细胞不结合。为了确定Fv - 4r env抗原与假定的MuLV受体的结合是否会阻断FLV感染，将预先用C4W血清孵育过的C3H胸腺细胞或脾细胞与FLV混合，并检测随后MuLV特异性抗原的产生。用C4W血清处理的C3H胸腺细胞或脾细胞对FLV的结合变得具有抗性。这些结果提供了证据，表明Fv - 4r env抗原在体内从C4W来源的细胞释放出来，并与表达亲嗜性MuLV表面受体的细胞结合，从而保护它们免受FLV感染。本文讨论了这些发现对逆转录病毒诱导疾病如获得性免疫缺陷综合征（AIDS）基因治疗的意义。
