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化科的逆转录病毒病科进行临床和实验室研究，目的是为艾滋病毒感染和与艾滋病有关的恶性肿瘤开发新的治疗方法。它还进行实验室研究，重点是了解这些疾病。在过去的一年里，该小组研究了67位和95位保守的半胱氨酸对HIV蛋白酶活性的作用。我们先前已经发现，Cys 95(在二聚体界面)的谷胱甘肽化可以取消HIV-1蛋白的活性，而Cys 67的谷胱甘肽化可以增强HIV-1的活性。已经产生了带有Cys95和Cys67突变的HIV病毒粒子，我们正在研究这些突变对HIV在不同条件下适应性的影响。我们最近发现，几乎所有的逆转录病毒蛋白水解酶都受二聚体界面可氧化氨基酸的调节，而在HIV-1的情况下，这是通过干扰二聚体的形成而发生的。一些对蛋白酶抑制剂产生抗药性的患者的艾滋病毒也被发现在Cys95上发生了突变，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是一个潜在的治疗靶点，我们正在试图设计作为这个位点的HIV蛋白酶抑制剂。我们还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)的发病机制中所起的作用。我们发现缺氧可以激活潜伏的KSHV进行裂解复制。我们发现有证据表明KSHV有三个基因在低氧条件下特异性上调：RTA、ORF34和病毒Bcl2。在一个案例中，我们已经在启动子区域发现了一个受缺氧诱导因子(HIF)上调的缺氧反应元件(HRE)。我们还在进行几项临床试验，以评估卡波西肉瘤的新疗法，重点是抗血管生成的方法。我们最近发现，在体外具有抗KSHV活性的抗疱疹药物西多福韦对KS患者没有诱导缓解作用。我们已经发现细胞因子IL-12在Kaposi肉瘤中具有长效活性的初步证据已经启动了一项试验，以研究IL-12和一种脂质体对晚期KS患者的联合治疗。我们还在研究抗血管内皮生长因子抗体作为KS的治疗剂，并计划进行一项试验，研究几种治疗Castleman病的试验性疗法。我们还与实验免疫学和移植科合作，研究将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，我们正在启动一项临床试验，以探索特定免疫能否发展到逆转录酶中的关键序列。