ONCOGENIC POTENTIAL OF HIV

HIV 的致癌潜力

• 批准号: 2114003
• 负责人: SUSAN M ASTRIN
• 金额: $ 35.2万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-09-30 至 1999-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2114003
• 关键词: AIDS; B lymphocyte; Epstein Barr virus; SCID mouse; clone cells; electroporation; human immunodeficiency virus 1; in situ hybridization; lymphoma; molecular oncology; neoplastic growth; neoplastic transformation; polymerase chain reaction; viral carcinogenesis; virus related neoplasm /cancer

Greater than twenty percent of HIV-1 infected will eventually develop a B-cell lymphoma. Historically, this incidence has been attributed to immune dysfunction and not to direct infection and transformation of B- cells by HIV. However, through the use of limiting dilution PCR (Polymerase Chain Reaction), a relatively new technique not previously applied to AIDS lymphomas, we have obtained evidence of a high load of HIV provirus in a subset (3 of 14) of AIDS-related B-cell lymphomas. These 3 tumors are all non-translocation cases. In addition, we have obtained evidence that these tumors are polyclonal which raises the possibility that transformation may be mediated by an HIV-specific protein. Furthermore, we have recently found that HIV can infect and malignantly transform B-cells populations in vitro (1,2), provided that at least some cells in the target population contain EBV. Our transformed line, B-HIV, contains one HIV provirus per cell and one EBV genome, grows in 1% serum, clones in soft agar, and forms malignant tumors in SCID mice. These results have led to the hypothesis that HIV infection of B- cells may in concert with EBV, can be a direct cause of a subset of AIDS- related lymphomas. Because this hypothesis is important and novel as well as controversial, the 4 aims of this proposal range from a more thorough analysis of B-cell tumor material, to the application of in situ hybridization for testing for the parallel presence of both HIV and EBV sequences, through to direct testing of the ability of HIV gene products to cause, in conjunction with EBV, the malignant transformation of B- cells. Our specific aims are: a. Analysis of additional AIDS B-cell lymphomas. b. Determination of the clonality of B-cell lymphomas containing a high load of HIV provirus. c. Detection of HIV and EBV in transformed cells and tumor cells by in situ hybridization. d. Use of a B-cell transformation assay to determine the gene(s) involved in malignant conversion in EBV infected B-cell populations. AIDS-related lymphomas represent a major cause of death for HIV-infected individuals. Our experiments are novel and have the potential of providing evidence of a mechanism by which HIV could transform B-cells in vivo generating lymphoma.

超过20%的HIV-1感染者最终会发展为 B细胞淋巴瘤从历史上看，这种发病率被归因于 免疫功能障碍，而不是直接感染和转化的B- 艾滋病毒的细胞。然而，通过使用有限稀释PCR， （聚合酶链反应），一种相对较新的技术，以前没有 应用于艾滋病淋巴瘤，我们已经获得了高负荷的证据， 艾滋病相关B细胞淋巴瘤亚组（3/14）中的HIV前病毒 这3例肿瘤均为非易位型。另外我们有 获得的证据表明，这些肿瘤是多克隆的， 转化可能是由HIV特异性 蛋白此外，我们最近发现艾滋病毒可以感染， 体外恶性转化B细胞群（1，2），前提是 靶群体中至少一些细胞含有EBV。我们的转变 B-HIV株，每个细胞含有一个HIV前病毒和一个EBV基因组， 在1%血清中，在软琼脂中克隆，并在SCID中形成恶性肿瘤 小鼠这些结果导致了这样的假设，即HIV感染B- 细胞可能与EB病毒一致，可能是艾滋病的一个子集的直接原因- 相关淋巴瘤因为这个假设很重要也很新颖 作为有争议的，这项建议的4个目标包括更彻底的 分析B细胞肿瘤材料，以应用于原位 用于检测HIV和EBV的平行存在的杂交 序列，通过直接测试HIV基因产物的能力 与EB病毒一起导致B- 细胞我们的具体目标是：a。额外的艾滋病B细胞分析 淋巴瘤B. B细胞淋巴瘤克隆性的测定 含有大量的HIV前病毒C. HIV和EBV的检测 转化细胞和肿瘤细胞的原位杂交。D.使用 B细胞转化试验，以确定参与 EBV感染的B细胞群的恶性转化。aids相关 淋巴瘤是HIV感染者死亡的主要原因。 我们的实验是新颖的，有可能提供证据， 艾滋病病毒在体内转化B细胞， 淋巴瘤