Department of Molecular Medicine, Mayo Clinic, Guggenheim 18-11c, 200 First Street, SW, Rochester, MN 55905, USA.
J Virol. 2011 Feb;85(3):1205-13. doi: 10.1128/JVI.00886-10. Epub 2010 Nov 17.
A novel gammaretrovirus, xenotropic murine leukemia virus-related virus (XMRV), has been identified in patients with prostate cancer and in patients with chronic fatigue syndromes. Standard Mus musculus laboratory mice lack a functional XPR1 receptor for XMRV and are therefore not a suitable model for the virus. In contrast, Gairdner's shrew-mice (Mus pahari) do express functional XPR1. To determine whether Mus pahari could serve as a model for XMRV, primary Mus pahari fibroblasts and mice were infected with cell-free XMRV. Infection of cells in vitro resulted in XMRV Gag expression and the production of XMRV virions. After intraperitoneal injection of XMRV into Mus pahari mice, XMRV proviral DNA could be detected in spleen, blood, and brain. Intravenous administration of a green fluorescent protein (GFP) vector pseudotyped with XMRV produced GFP(+) CD4(+) T cells and CD19(+) B cells. Mice mounted adaptive immune responses against XMRV, as evidenced by the production of neutralizing and Env- and Gag-specific antibodies. Prominent G-to-A hypermutations were also found in viral genomes isolated from the spleen, suggesting intracellular restriction of XMRV infection by APOBEC3 in vivo. These data demonstrate infection of Mus pahari by XMRV, potential cell tropism of the virus, and immunological and intracellular restriction of virus infection in vivo. These data support the use of Mus pahari as a model for XMRV pathogenesis and as a platform for vaccine and drug development against this potential human pathogen.
一种新型γ逆转录病毒，嗜性骨髓细胞瘤病毒相关病毒（XMRV），已在前列腺癌患者和慢性疲劳综合征患者中被发现。标准的实验室小鼠 Mus musculus 缺乏功能性 XPR1 受体，因此不适合作为该病毒的模型。相比之下，Gairdner's shrew-mice（Mus pahari）确实表达功能性 XPR1。为了确定 Mus pahari 是否可以作为 XMRV 的模型，我们用无细胞的 XMRV 感染了原代 Mus pahari 成纤维细胞和小鼠。体外细胞感染导致 XMRV Gag 表达和 XMRV 病毒粒子的产生。将 XMRV 经腹腔注射到 Mus pahari 小鼠中后，可在脾脏、血液和大脑中检测到 XMRV 前病毒 DNA。静脉注射用 XMRV 假型化的绿色荧光蛋白（GFP）载体，可产生 GFP(+) CD4(+) T 细胞和 CD19(+) B 细胞。实验表明，XMRV 感染小鼠产生了针对 XMRV 的适应性免疫反应，产生了中和抗体和针对 Env 和 Gag 的特异性抗体。从脾脏分离的病毒基因组中还发现了显著的 G-to-A 超突变，提示 APOBEC3 在体内限制了 XMRV 的感染。这些数据表明 XMRV 感染了 Mus pahari，该病毒具有潜在的细胞嗜性，并且在体内病毒感染受到免疫和细胞内的限制。这些数据支持使用 Mus pahari 作为 XMRV 发病机制的模型，并作为针对这种潜在人类病原体的疫苗和药物开发的平台。
