ANTIVIRAL RESISTANCE IN AIDS

艾滋病的抗病毒耐药性

• 批准号: 6510436
• 负责人: DOUGLAS D RICHMAN
• 金额: $ 39.38万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-09-30 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6510436
• 关键词: AIDS therapy; Alphaherpesvirinae; HIV infections; Herpesviridae disease; RNA directed DNA polymerase; acyclovir; antiAIDS agent; antisense nucleic acid; cytomegalovirus; drug design /synthesis /production; drug resistance; enzyme deficiency; human immunodeficiency virus; human tissue; nucleoside analog; opportunistic infections; protease inhibitor; reverse transcriptase inhibitors; ribozymes; tissue /cell culture; tumor necrosis factor alpha; zidovudine

Over 1,000,000 Americans and 15 million individuals worldwide are infected with HlV. These numbers have been projected to be in the range of 40 - 100 million by the year 2000. Chemotherapeutic suppression of viral replication provides the greatest likelihood of beneficial intervention in the natural history of disease progression, at least for the near future. Three nucleoside analogs (zidovudine [AZT], dideoxyinosine [ddI], and dideoxycytosine [ddC]) have been approved for use in the United States. In certain patient populations these can prolong life and reduce morbidity; nevertheless, much room for improvement remains. In addition, herpesviruses (HSV, VZV, and CMV) represent the most prevalent and significant opportunistic viral complications of HIV disease. The identification of effective drug regimens for both HIV and the herpesviruses must contend with a number of hurdles. One of the most important of these is drug resistance. The objectives of this proposal are to characterize the expression, the genetic basis, the mechanisms, and approaches to treat antiviral drug resistance. Specific aims include 1) the investigation of the nature and significance of nucleoside drug resistance, 2) the confirmation or denial of the hypothesis that higher plasma levels of non-nucleoside reverse transcriptase inhibitors can effectively suppress drug resistant virus, 3) the determination whether the clinical failure of the tat antagonist Ro 24-7429 is attributable to TNFalpha and whether inhibitors of TNFalpha can synergize tat antagonist activity, 4) to examine drug resistance with protease inhibitors, 5) to determine whether HIV gene therapies, like antisense oligonucleotides and ribozymes, can select for escape mutants (resistance), and 6) to develop compounds that effectively bypass drug resistance caused by acquired or innate kinase deficiencies of herpesviruses like HSV and CMV. These studies involving both specimens from clinical investigations and more basic molecular biologic and biochemical approaches are intended to elucidate new approaches to treat HIV and opportunistic herpesvirus infections more effectively.

全球超过100万美国人和1500万个人被感染 与HLV。这些数字预计将在40-100范围内 到2000年，百万。化学治疗抑​​制病毒 复制提供了有益干预的最大可能性 疾病进展的自然历史，至少在不久的将来。 三个核苷类似物（Zidovudine [azt]，二氧基氨酸[DDI]和 甲氧基胞嘧啶[DDC]）已被批准在美国使用。在 某些患者人群这些可以延长寿命并降低发病率； 然而，仍然有很多改进的余地。此外， 疱疹病毒（HSV，VZV和CMV）代表最普遍的 艾滋病毒疾病的重要机会病毒并发症。这 鉴定艾滋病毒和艾滋病毒的有效药物方案 疱疹病毒必须与许多障碍抗衡。最大的 其中重要的是耐药性。 该提案的目标是表征表达， 遗传基础，机制和治疗抗病毒药的方法 反抗。具体目的包括1）对性质的调查 核苷耐药性的重要性，2）确认或否认 假设较高的血浆水平的非核苷反面 转录酶抑制剂可以有效抑制抗药性病毒，3） TAT拮抗剂RO的临床失败是否确定 24-7429归因于tnfalpha，tnfalpha的抑制剂是否可以 协同化TAT拮抗剂活性，4）检查使用耐药性 蛋白酶抑制剂，5）确定HIV基因疗法是否像 反义寡核苷酸和核酶可以为逃生突变体选择 （电阻）和6）开发有效绕过药物的化合物 因获得或先天激酶缺陷引起的阻力 HSV和CMV等疱疹病毒。 这些研究涉及临床研究和 更基本的分子生物学和生化方法旨在 阐明治疗艾滋病毒和机会主义疱疹病毒的新方法 感染更有效。