DEVELOPMENT OF NOVEL THERAPIES FOR HIV INFECTION & RELATED MALIGNANCIES

HIV 感染新疗法的开发

• 批准号: 2464462
• 负责人: R YARCHOAN
• 金额: --
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 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/2464462
• 关键词: 2'3' dideoxynucleoside; AIDS related neoplasm /cancer; AIDS therapy; HIV infections; Herpesviridae; Kaposi's sarcoma; angiogenesis; antiviral agents; antiviral antibody; clinical research; clinical trials; combination chemotherapy; cysteine; drug screening /evaluation; enzyme activity; helper T lymphocyte; human immunodeficiency virus; human subject; human therapy evaluation; paclitaxel; protease inhibitor; thalidomide; viral vaccines; zidovudine

The Retroviral Diseases Section conducts translational clinical and laboratory research aimed at the development of novel therapies for HIV infection and AIDS-related malignancies. It also conducts laboratory research focused on an understanding of these diseases. During the past year, the group has investigated the role of a newly discovered herpesvirus, called Kaposi's sarcoma-associated herpesvirus (KSHV) or human herpesvirus-8 (HHV-8), in the pathogenesis of Kaposi's sarcoma (KS). We have found that this virus persists in the lymphocytes of patients receiving anti-herpes therapy. However, it is possible that replicating virus is important in the pathogenesis of KS, and a study is being planned to examine an anti-herpes drug in patients with KS and relatively high CD4 cells. In addition, we have developed a serologic assay to detect antibodies to a lytic antigen of this virus. We are conducting several clinical trials to evaluate novel therapies for Kaposi's sarcoma, including the anti-angiogenesis inhibitors TNP-470 and thalidomide, and paclitaxel. We have found that paclitaxel is one of the most active single drugs in patients with advanced KS. The response rate in this population is approximately 75%, and this includes several patients with pulmonary KS. In the laboratory, we are studying the differential ability of Th-1 and Th-2 T cells to be infected by HIV. In regard to anti-HIV therapy, we are conducting several laboratory studies of HIV protease and protease inhibitors. We have found that immature HIV virions produced in the presence of protease inhibitors do not go on to mature to infectious particles once the inhibitors are washed out. In addition, studies are underway to study the role of cysteines at positions 67 and 95 to the activity of HIV protease. We have found that lutathiolation of Cys 95 abolishes HIV protease activity, while glutathiolation of Cys 67 can enhance activity. This may provide a target for anti-HIV therapy. In the clinic, we are testing KNI-272, a novel HIV protease inhibitor; AZT plus bis-POM PMEA, a peptide HIV envelope vaccine; and beta-fluoro-ddA, a novel reverse transcriptase inhibitor.

逆转录病毒疾病部门进行转化临床和 实验室研究旨在开发新的艾滋病毒疗法 感染和与艾滋病有关的恶性肿瘤。 它还进行实验室 研究重点是对这些疾病的理解。 在过去 一年，该小组调查了新发现的角色 疱疹病毒，称为Kaposi的肉瘤相关疱疹病毒（KSHV）或 人类疱疹病毒8（HHV-8），在卡波西肉瘤（KS）的发病机理中。 我们发现该病毒持续存在于患者的淋巴细胞中 接受抗主疱疹疗法。 但是，有可能复制 病毒在KS的发病机理中很重要，并且正在计划进行研究 检查KS患者和CD4较高的患者的抗疱疹药物 细胞。 此外，我们开发了一种血清学分析来检测 该病毒溶液抗原的抗体。 我们正在进行几个 评估卡波西肉瘤的新疗法的临床试验， 包括抗血管生成抑制剂TNP-470和沙利度胺，以及 紫杉醇。 我们发现紫杉醇是最活跃的 晚期KS患者的单一药物。 回应率 人口约为75％，其中包括几名患者 肺部KS。 在实验室中，我们正在研究差异能力 由HIV感染的Th-1和Th-2 T细胞 关于抗HIV 治疗，我们正在进行几项有关HIV蛋白酶和的实验室研究 蛋白酶抑制剂。 我们发现在 蛋白酶抑制剂的存在不会继续成熟到感染性 颗粒一旦抑制剂被洗净。 此外，研究是 正在研究半胱氨酸在67和95位置的作用 HIV蛋白酶的活性。 我们发现CYS 95的鲁硫酸化 废除HIV蛋白酶活性，而Cys 67的谷胱甘肽化可以 增强活动。 这可能为抗HIV治疗提供了一个靶标。 在 诊所，我们正在测试一种新型HIV蛋白酶抑制剂KNI-272。 AZT Plus BIS-POM PMEA，一种肽HIV包膜疫苗；和beta-fluoro-dda，一本小说 逆转录酶抑制剂。