Development of Novel Therapies for HIV Infection and Related Malignancies

HIV 感染及相关恶性肿瘤新疗法的开发

• 批准号: 6433120
• 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/6433120
• 关键词: 2'3' dideoxynucleoside; AIDS related neoplasm /cancer; AIDS therapy; AIDS vaccines; HIV infections; Kaposi's sarcoma; angiogenesis; angiogenesis inhibitors; antiviral agents; clinical research; clinical trials; combination chemotherapy; cysteine; cytokine; enzyme activity; helper T lymphocyte; human herpesvirus 8; human immunodeficiency virus 1; human subject; human therapy evaluation; interleukin 12; protease inhibitor; sulfur group transferase; thalidomide; virion

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 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 preliminary results showing 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 in the process of extending these observations to the proteases of other retroviruses. Also, we are attempting to design inhibitors of HIV protease that act through binding to these conserved cysteines. Other laboratory studies have involved a study of the differential ability of protease inhibitors in monocytes and lymphocytes and the mechanisms that might cause these differences. We have also continued the investigation of the combined activity of a newly discovered herpesvirus, called Kaposi's sarcoma-associated herpesvirus (KSHV) or human herpesvirus-8 (HHV-8), and HIV in the pathogenesis of Kaposi's sarcoma (KS). In particular, we are studying factors that induce the activation of this virus. 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 obtained preliminary results indicating that the anti-angiogenesis agent thalidomide is active in a subset of patients with Kaposi's sarcoma. We are also studying IL-12 for possible activity in Kaposi's sarcoma and also the anti- herpes drug cidofovir and its effect on the expression of KSHV-related genes in KS. We have initiated a trial to investigate the mechanisms by which anti-HIV therapy may benefit KS. Studies are planned to investigate the novel angiogenesis inhibitor SU-6668 and the combination of IL-12 and a liposomal anthracycline in 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的谷胱甘肽化消除了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，并具有初步的结果表明，HIV-2的位置上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。 我们正在将这些观察结果扩展到其他逆转录病毒的蛋白酶。 此外，我们正在尝试设计通过与这些保守的半胱氨酸结合起来的HIV蛋白酶抑制剂。 其他实验室研究涉及对单核细胞和淋巴细胞中蛋白酶抑制剂的差异能力的研究以及可能导致这些差异的机制。我们还继续研究了新发现的疱疹病毒的合并活性，称为Kaposi肉瘤相关的疱疹病毒（KSHV）或人类疱疹病毒8（HHV-8）（HHV-8）和HIV，在Kaposi的Sarcoma（KS）中。 特别是，我们正在研究诱导该病毒激活的因素。 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。我们最近获得了初步结果，表明抗血管生成剂沙利度胺在Kaposi肉瘤患者的一部分中活跃。我们还正在研究IL-12在Kaposi的肉瘤和抗疱疹药物Cidofovir中可能活性，及其对KSH与KSH相关基因在KS中表达的影响。 我们已经开始了一项试验，以研究抗HIV治疗可能受益KS的机制。 计划研究新型血管生成抑制剂SU-6668，以及IL-12和KS中IL-12和脂质体蒽环素的组合。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