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: 6756297
• 负责人: ROBERT 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/6756297
• 关键词: AIDS related neoplasm /cancer; AIDS therapy; AIDS vaccines; Kaposi's sarcoma; angiogenesis inhibitors; antiviral agents; clinical trials; combination chemotherapy; cysteine; endopeptidases; enzyme activity; gene mutation; glutathione; helper T lymphocyte; human herpesvirus 8; human subject; human therapy evaluation; interleukin 12; lymphoma; neoplasm /cancer immunotherapy; oxidative stress; patient oriented research; protease inhibitor; protein structure function; synthetic vaccines; vaccine development; virus protein

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 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 are exploring the regulation of HIV-2 protease and have found that a methionine in position 95 of HIV-2 acts in a way similar to the cysteine in position 95 of HIV-1 in terms of regulating the protease activity. We are studying the mechanism for this regulation and assessing whether this is a general mechanism for regulation of retroviral proteases. 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 are currently exploring the mechanism for the effect, and have preliminary evidence that at least two genes of KSHV have functional hypoxia response elements (HRE) in their promoter regions that respond to increased cellular levels of hypoxia inducible factors (HIFs). 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. A separate clinical trial, however, provided evidence that the anti-angiogenesis agent thalidomide is active in a subset of patients with KS. We are also exploring the relationship between anti-HIV therapy and 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 infusional chemotherapy and IL-12 as therapy for AIDS-associated lymphoma. In regard to anti-HIV therapy, a clinical trial is under way to study two HIV envelope peptide vaccines in HIV-infected patients in combination with highly active antiretroviral therapy. Preliminary results indicate that the vaccine can boost proliferative T cell responses against HIV in a majority of patients. A study is planed to investigate a vaccinia-virus based HIV vaccine. 100% AIDS related

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。我们发现，Cys 95（在二聚体界面中）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。我们正在探索HIV-2蛋白酶的调节，并发现HIV-2位置的蛋氨酸在调节蛋白酶活性方面以类似于HIV-1位置的半胱氨酸的方式起作用95位。我们正在研究该调节的机制，并评估这是否是调节逆转录病毒蛋白酶的一般机制。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。我们目前正在探索该作用的机制，并有初步证据表明，至少两个KSHV基因在其启动子区域中具有功能性缺氧反应元件（HRE），这些响应因子的细胞水平增加（HIF）。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。然而，另一项临床试验提供了证据表明抗血管生成剂沙利度胺在KS患者的一部分中活跃。我们还正在探索抗HIV疗法与KS之间的关系。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。我们还研究了输注化疗和IL-12作为与艾滋病相关淋巴瘤的治疗。关于抗HIV疗法，正在进行一项临床试验，以研究HIV感染患者的两种HIV包膜肽疫苗，并结合高度活性的抗逆转录病毒疗法。初步结果表明，在大多数患者中，疫苗可以提高针对HIV的增殖T细胞反应。计划研究基于疫苗的HIV疫苗。 100％艾滋病