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: 7292022
• 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/7292022
• 关键词: Development; Novel; Therapies; HIV; Infection

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 a conserved cysteine at position 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. HIV virions with mutations of Cys 95 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 Kaposi's sarcoma-associated herpes virus (KSHV), also called 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 several genes of KSHV are specifically upregulated by hypoxia. Two of these genes are Rta and viral Bcl-2. We had previously found that a gene of unknown function, ORF34, is specifically activated by hypoxia. ORF34 is part of a cluster of genes (ORF34 to 37), and we are currently analyzing the structure of this cluster cluster and their regulation by hypoxia. One of these genes, ORF36, can phosphorylate ganciclovir, and activation of this gene by hypoxia may be able to be used to therapeutic benefit in KSHV-associated tumors, especially PEL. As an outgrowth of the work on hypoxia and its effects on KSHV, we have also explored the differential activity of hypoxia inducible factors (HIF) 1 (HIF-1) and 2 (HIF-2) on the activation of cellular genes, and have identified a number of genes that are selectively activated by either HIF-1 or HIF-2. We are also conducting several clinical trials to evaluate novel therapies for Kaposi's sarcoma with a focus on anti-angiogenesis approaches. We have found that the cytokine IL-12 has long-acting activity in Kaposi's sarcoma have also conducted 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. We have initiated trials to study the natural history study of multicentric Castleman's disease (MCD), which is also caused by KSHV and plan to explore a therapeutic strategy involving antiviral drugs activated by KSHV. We have also recently initiated a trial studying novel approaches involving KSHV gene activation and then cytotoxic chemotherapy in primary effusion lymphoma (PEL). 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 crucial 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，该小组调查了在95位置在HIV蛋白酶活性的位置上保守的半胱氨酸的作用。以前，我们已经发现Cys 95（在二聚体界面中）的谷胱甘肽消除了HIV-1蛋白酶活性。已经产生了具有CYS 95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Kaposi肉瘤相关的疱疹病毒（KSHV）的作用，也称为人类疱疹病毒8（HHV-8）在Kaposi的肉瘤（KS）的发病机理中的作用。我们发现缺氧可以激活潜在的KSHV进行裂解复制。我们发现有证据表明，多氧人物特异性地上调了一些KSHV基因。这些基因中的两个是RTA和病毒Bcl-2。我们以前已经发现，未知功能的基因ORF34是由缺氧专门激活的。 ORF34是基因群（ORF34至37）的一部分，我们目前正在分析该簇簇的结构及其对缺氧的调节。这些基因之一，ORF36，可以磷酸化ganciclovir，而缺氧对该基因的激活可以用于与KSHV相关的肿瘤（尤其是PEL）中的治疗益处。作为缺氧及其对KSHV的影响的产物，我们还探讨了缺氧诱导因子（HIF）1（HIF-1）（HIF-1）和2（HIF-2）对细胞基因激活的差异活性，并确定了许多由HIF-1或HIF-1选择性激活的基因。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。我们发现，Cytokine IL-12在Kaposi的肉瘤中具有长效活性，还进行了一项试验，研究了晚期KS患者的IL-12和脂质体蒽环素的组合。我们还正在研究KS中VEGF的抗体。我们已经开始了研究多中心Castleman病（MCD）的自然史研究，该研究也是由KSHV引起的，并计划探索涉及KSHV激活的抗病毒药物的治疗策略。我们最近还开始了一项试验，研究了涉及KSHV基因激活的新方法，然后在一级积液淋巴瘤（PEL）中进行了细胞毒性化学疗法。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关键序列开发特定的免疫力。