MECHANISMS OF PATHOGENESIS AND RECOVERY IN FRIEND RETROVIRUS-INDUCED LEUKEMIA

FRIEND逆转录病毒引起的白血病的发病机制和恢复机制

• 批准号: 5200390
• 负责人: B W CHESEBRO
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/5200390
• 关键词: Friend leukemia; Friend virus; MHC class I antigen; gene induction /repression; heterozygote; immunogenetics; immunoglobulin G; laboratory mouse; major histocompatibility complex; microorganism immunology; viral vaccines; virulence; virus antigen; virus envelope; virus genetics; virus infection mechanism; virus protein

Friend virus (FV) is a complex of 2 mouse retroviruses which induce rapid erythroleukemia in many strains of adult mice. Various genes in susceptible mice can modify the outcome of FV infection. Our laboratory has identified 5 such genes including 4 major histocompatibility complex (MHC) regions (D, IA, IE and T) and one non-MHC gene, Rfv-3. These genes all influence the host immune response to FV and FV leukemia cells and can even induce spontaneous recovery from leukemia or facilitate successful protective vaccination against challenge with live FV or FV leukemia cells. This year, using microsatellite mapping methods, the location of the Rfv- 3 gene was identified to be on mouse chromosome 15. Rfv-3 is known to influence the ability of mice to make a humoral antibody response to FV during the course of active infection. Mice with the Rfv-3r allele make anti-FV antibodies and clear FV viremia 2-3 weeks after infection. This is necessary, but not sufficient, for recovery from FV leukemia. The mechanism of the Rfv-3 gene function on the host immune response is not known, but the location of the gene indicates that it is near a T cell antigen gene (Ly6) and 3 cytokine receptor genes (IL2rb, IL3rb1, and IL3rb2). Future experiments will be aimed at identifying the mechanism of action of this gene. Other experiments have shown that mice lacking the Rfv-3r allele can still recover from FV leukemia if they are inoculated with high doses of anti-FV antibody. This antibody therapy was effective even if initiated after the peak of virus spread in vivo. However, recovery associated with antibody therapy also required T cell-mediated immune mechanisms because no recovery was observed in CD4- or CD8-depleted mice. These results indicate that recovery from Friend retroviral infection is dependent on the cooperative effects of several difference immune mechanisms including T helper cells, cytotoxic T and antibodies, and antibodies. The results imply that similar mechanisms might be effective in treatment of HIV infection with antibody therapy.

Friend病毒（FV）是由两种小鼠逆转录病毒组成的复合体， 红白血病在许多品系的成年小鼠。 中各种基因 易感小鼠可以改变FV感染的结果。 本实验室 已经鉴定了5个这样的基因，包括4个主要组织相容性复合体 (MHC)区域（D、IA、IE和T）和一个非MHC基因Rfv-3。 这些基因 都影响宿主对FV和FV白血病细胞的免疫应答， 甚至可以诱导白血病的自发恢复， 针对活FV或FV攻击的成功保护性疫苗接种 白血病细胞 今年，利用微卫星测绘方法，Rfv的位置- 3基因位于小鼠15号染色体上。 Rfv-3已知 影响小鼠对FV产生体液抗体应答的能力 在活动性感染的过程中。 携带Rfv-3r等位基因的小鼠 感染后2-3周出现抗FV抗体和明确的FV病毒血症。 这 是从FV白血病中恢复所必需的，但不是充分的。 的 Rfv-3基因在宿主免疫应答中的作用机制并不清楚， 已知，但该基因的位置表明它靠近T细胞 抗原基因（Ly 6）和3种细胞因子受体基因（IL 2 rb，IL 3rb 1， IL3rb2）。 未来的实验将旨在确定其机制 这个基因的作用。 其他实验表明，缺乏Rfv-3r等位基因的小鼠可以 如果他们接种高剂量的 抗FV抗体。 这种抗体治疗是有效的，即使开始 病毒在体内传播高峰后。 然而，恢复相关 抗体治疗也需要T细胞介导的免疫机制 因为在CD 4或CD 8耗尽的小鼠中没有观察到恢复。 这些 结果表明，从Friend逆转录病毒感染中恢复， 依赖于几种不同免疫的协同作用， 机制包括T辅助细胞、细胞毒性T和抗体，以及 抗体的 结果表明，类似的机制可能是有效的 用抗体疗法治疗HIV感染。