Development of Novel Therapies for HIV Infection and AID

HIV 感染和艾滋病新疗法的开发

• 批准号: 6947459
• 负责人: Antonio Fojo
• 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/6947459
• 关键词: AIDS related neoplasm /cancer; AIDS therapy; HIV infections; Kaposi's sarcoma; angiogenesis inhibitors; antiAIDS agent; antineoplastics; antiviral agents; biotherapeutic agent; cysteine; drug resistance; drug screening /evaluation; enzyme activity; gene mutation; glutathione; human herpesvirus 8; human subject; human therapy evaluation; hypoxia; hypoxia inducible factor 1; interleukin 12; neoplasm /cancer blood supply; neoplasm /cancer genetics; neoplasm /cancer immunotherapy; oxidative stress; patient oriented research; protease inhibitor; vascular endothelial growth factors; virus protein; virus related neoplasm /cancer; AIDS related neoplasm /cancer; AIDS therapy; HIV infections; Kaposi's sarcoma; angiogenesis inhibitors; antiAIDS agent; antineoplastics; antiviral agents; biotherapeutic agent; cysteine; drug resistance; drug screening /evaluation; enzyme activity; gene mutation; glutathione; human herpesvirus 8; human subject; human therapy evaluation; hypoxia; hypoxia inducible factor 1; interleukin 12; neoplasm /cancer blood supply; neoplasm /cancer genetics; neoplasm /cancer immunotherapy; oxidative stress; patient oriented research; protease inhibitor; vascular endothelial growth factors; virus protein; virus related neoplasm /cancer

The Retroviral Diseases Section of the HIV and AIDS Malignancy Branch 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 conserved cysteines at positions 67 and 95 on the activity of HIV protease. We have previously found that glutathiolation of Cys 95 (in the dimer interface) abolishes HIV-1 protease activity, while glutathiolation of Cys 67 can enhance activity. HIV virions with mutations of Cys 95 and Cys67 have been generated and we are studying the effects that these mutations have on the fitness of HIV under varying conditions. We have recently found that nearly all retroviral proteases are regulated by oxidizable amino acids at the dimer interface and that in the case of HIV-1, this occurs by interfering with dimer formation. HIV from some patients who have developed resistance to protease inhibitors have been also found to develop a mutation in Cys95, and we are trying to understand the evolutionary pressures leading to this mutation. This work on HIV protease has identified the dimer interface as a potential therapeutic target, and we are attempting to design inhibitors of HIV protease that act as this site. We are also investigating 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 hypoxia can activate latent KSHV to undergo lytic replication. We have found evidence that three genes of KSHV are specifically upregulated by hypoxia: Rta, ORF34, and viral Bcl-2. In one case, we have identified a hypoxia responsive element (HRE) in the promoter region that is upregulated by hypoxia inducible factor (HIF). We are also conducting several clinical trials to evaluate novel therapies for Kaposi's sarcoma with a focus on anti-angiogenesis approaches. We have recently found that the anti-herpes drug cidofovir, which has in vitro activity against KSHV, does not induce remissions in patients with KS. We have found preliminary evidence that the cytokine IL-12 has long-acting activity in Kaposi's sarcoma have initiated a trial to study the combination of IL-12 and a liposomal anthracycline in patients with advanced KS. We are also studying antibody to VEGF as a therapeutic agent in KS and are planning a trial to study several pilot therapies for Castleman's disease. We are also studying infusional chemotherapy as therapy for AIDS-associated lymphoma in collaboration with the Experimental Immunology and Transplantation Branch. In regard to anti-HIV therapy, we are initiating a clinical trial to explore whether specific immunity can be developed to a cruical sequence in reverse transcriptase.

HIV和AIDS恶性分支的逆转录病毒疾病部分进行转化临床和实验室研究，旨在开发用于HIV感染和与AIDS相关的恶性肿瘤的新疗法。它还进行了专注于对这些疾病的理解的实验室研究。在过去的一年中，该小组研究了在67和95位置在HIV蛋白酶活性方面的保守半胱氨酸的作用。我们以前已经发现，Cys 95（在二聚体界面）的谷胱甘肽化废除了HIV-1蛋白酶活性，而CYS 67的谷氨酸化可以增强活性。已经产生了具有CYS 95和CYS67突变的HIV病毒体，我们正在研究这些突变对不同条件下HIV的适应性的影响。我们最近发现，几乎所有逆转录病毒蛋白酶都受二聚体界面处的可氧化氨基酸调节，在HIV-1的情况下，这是通过干扰二聚体形成而发生的。一些患者的HIV也发现对蛋白酶抑制剂产生了抗性，也发现在Cys95中会发生突变，我们正在尝试了解导致这种突变的进化压力。有关HIV蛋白酶的这项工作已将二聚体界面确定为潜在的治疗靶点，我们正在尝试设计起作用的HIV蛋白酶的抑制剂。我们还正在研究新发现的疱疹病毒的作用，称为卡波西肉瘤相关的疱疹病毒（KSHV）或人类疱疹病毒8（HHV-8）在卡波西肉瘤（KS）的发病机理中。我们发现缺氧可以激活潜在的KSHV进行裂解复制。我们发现证据表明，三个KSHV基因由缺氧特异性上调：RTA，ORF34和病毒BCL-2。在一种情况下，我们已经确定了启动子区域中的缺氧反应元件（HRE），该元件被低氧诱导因子（HIF）上调。我们还进行了几项临床试验，以评估Kaposi肉瘤的新疗法，重点是抗血管生成方法。我们最近发现，具有针对KSHV的体外活性的抗疱疹药物Cidofovir不会引起KS患者的缓解。我们发现了初步证据表明，Cytokine IL-12在Kaposi的肉瘤中具有长效活性，已经开始了一项试验，研究了晚期KS患者的IL-12和脂质体蒽环类素的组合。我们还正在研究KS中VEGF的抗体，并计划一项试验，以研究Castleman病的几种试点疗法。我们还研究了与实验免疫学和移植分支合作的IADS相关淋巴瘤治疗的输液化疗。关于抗HIV疗法，我们正在启动一项临床试验，以探讨是否可以针对逆转录酶中的巡游序列开发特定的免疫力。