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

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.

艾滋病毒和艾滋病恶性肿瘤分支的逆转录病毒疾病科进行转化临床和实验室研究，旨在开发艾滋病毒感染和艾滋病相关恶性肿瘤的新型疗法。它还进行实验室研究，重点是了解这些疾病。在过去的一年中，该小组研究了67和95位保守半胱氨酸对HIV蛋白酶活性的作用。我们以前已经发现，谷胱甘肽的Cys 95（在二聚体界面）废除HIV-1蛋白酶活性，而谷胱甘肽的Cys 67可以增强活性。已经产生了具有Cys 95和Cys 67突变的HIV病毒体，我们正在研究这些突变在不同条件下对HIV适应性的影响。我们最近发现，几乎所有的逆转录病毒蛋白酶的二聚体界面的可氧化氨基酸的调节，并在HIV-1的情况下，这是通过干扰二聚体的形成。来自一些对蛋白酶抑制剂产生耐药性的患者的HIV也被发现在Cys 95中产生突变，我们正在试图了解导致这种突变的进化压力。这项关于HIV蛋白酶的工作已经确定了二聚体界面作为一个潜在的治疗靶点，我们正在尝试设计HIV蛋白酶的抑制剂，作为这个网站。我们也正在研究一种新发现的疱疹病毒，称为卡波西肉瘤相关疱疹病毒（KSHV）或人类疱疹病毒-8（HHV-8），在卡波西肉瘤（KS）发病机制中的作用。我们已经发现，缺氧可以激活潜伏的KSHV进行裂解复制。我们已经发现证据表明，KSHV的三个基因特异性上调缺氧：Rta，ORF 34和病毒Bcl-2。在一种情况下，我们已经确定了一个缺氧反应元件（HRE）的启动子区，是由缺氧诱导因子（HIF）上调。我们还进行了几项临床试验，以评估卡波西肉瘤的新疗法，重点是抗血管生成方法。我们最近发现，抗疱疹药物西多福韦（cidofovir）在体外对KSHV具有活性，但在KS患者中不会引起缓解。我们已经发现了细胞因子IL-12在卡波西肉瘤中具有长效活性的初步证据，已经开始了一项研究IL-12和脂质体蒽环类药物联合治疗晚期KS患者的试验。我们也在研究VEGF抗体作为KS的治疗剂，并计划进行一项试验，研究Castleman病的几种试点疗法。我们还与实验免疫学和移植分支合作，研究注射化疗作为艾滋病相关淋巴瘤的治疗方法。在抗HIV治疗方面，我们正在开展一项临床试验，以探索是否可以对逆转录酶中的关键序列产生特异性免疫。