MOLECULAR BASIS FOR THE PATHOGENICITY OF MURINE RETROVIRUSES

利用小鼠模型系统来研究免疫调节的分子基础。 某些逆转录病毒的发病机制。 含gag-myb-ets的ME26 病毒导致小鼠白血病的高发病率。 体内和 在体外，ME26病毒感染导致造血细胞活化， 某些红系特异性基因的前体细胞，如加塔-1、Epo 受体和珠蛋白，而不是其他。 反式激活研究表明 ME 26病毒基因产物反式激活加塔-1基因， 与加塔-1蛋白协同反式激活Epo受体基因。 DNA结合研究表明，ME26病毒基因产物特异性 与加塔-1启动子结合。 利用突变病毒基因组的研究 表明病毒myb和ets区域的变化可以 改变其生物活性，并且v-myb和v-ets基因必须 表达为融合基因产物以具有生物学效应。 这些 研究表明，ME26病毒通过一种新的 涉及增殖和分化的解偶联的机制。 PVC-211小鼠白血病病毒（MuLV）是一种神经致病性弱- 非神经致病性高度致白血病的 朋友MuLV。 利用嵌合病毒的研究表明， 编码蛋白质受体结合区的env基因， 包含了负责组织病理变化的决定因素， 中枢神经系统（CNS）。 当测试病毒的能力时， 为了在培养的脑毛细血管内皮细胞（BCEC）中复制， 在CNS内PVC-211 MuLV复制的主要位点， 病毒在BCEC中的复制效率与 和其在体内引起神经系统疾病的能力。 这些 研究表明，PVC-211 MuLV中使其 神经致病性影响其在BCEC中的复制，并表明有效 病毒在BCEC中的复制对BCEC的病理变化至关重要。 导致神经系统疾病CNS。

Mouse model systems are utilized to study the molecular basis for the pathogenesis of certain retroviruses. The gag-myb-ets-containing ME26 virus causes a high incidence of leukemia in mice. Both in vivo and in vitro, ME26 virus infection leads to the activation in hematopoietic precursor cells of certain erythroid-specific genes, such as GATA-1, Epo receptor, and globin, but not others. Transactivation studies indicate that the ME26 viral gene product transactivates the GATA-1 gene and then cooperates with the GATA-1 protein to transactivate the Epo receptor gene. DNA-binding studies show that the ME26 viral gene product specifically binds to the GATA-1 promoter. Studies utilizing mutated viral genomes suggest that changes in both the myb and ets regions of the virus can alter its biological activity and that both the v-myb and v-ets genes must be expressed as a fusion gene product to have a biological effect. These studies indicate that ME26 virus induces leukemia in mice by a novel mechanism involving the uncoupling of proliferation and differentiation. PVC-211 murine leukemia virus (MuLV) is a neuropathogenic, weaky- leukemogenic variant of the non-neuropathogenic, highly-leukemogenic Friend MuLV. Studies utilizing chimeric viruses indicate that the 5' half of the env gene, which encodes the receptor binding region of the protein, contains the determinant(s) responsible for pathological changes in the central nervous system (CNS). When viruses were tested for their ability to replicate in cultured brain capillary endothelial cells (BCEC), the primary site of PVC-211 MuLV replication within the CNS, there was a direct correlation between the replication efficiency of the virus in BCEC in vitro and its ability to cause neurological disease in vivo. These studies indicate that the sequences in PVC-211 MuLV which render it neuropathogenic affect its replication in BCEC and suggest that efficient viral replication in BCEC is crucial for the pathological changes in the CNS that result in neurological disease.