Control of HIV drug resistance in older patients

老年患者艾滋病毒耐药性的控制

• 批准号: 7753133
• 负责人: Alonso Heredia
• 金额: $ 7.5万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-22 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7753133
• 关键词: Affect; Affinity; Aging; Anti-Retroviral Agents; Antibodies; Binding; Biological Assay; CCR5 gene; Cell Line; Cell fusion; Cells; Chemokine (C-C Motif) Receptor 5; Clinical Trials; Comorbidity; Cytochrome P450 3A4; Development; Dose; Drug Delivery Systems; Drug Interactions; Drug resistance; Educational workshop; Elderly; Goals; HIV; HIV Envelope Protein gp120; HIV Infections; HIV drug resistance; Heart; Highly Active Antiretroviral Therapy; In Vitro; Individual; Infection; Inosine Monophosphate; Integrase; Kidney; Length; Licensing; Life; Life Cycle Stages; Life Expectancy; Ligands; Liver diseases; Metabolism; Mutate; Mycophenolic Acid; National Institute of Allergy and Infectious Disease; Nature; Nucleosides; Oxidoreductase; Patients; Pharmaceutical Preparations; Phase; Phase III Clinical Trials; Predisposition; Protease Inhibitor; Proteins; Quality of life; RANTES; RNA Interference; RNA-Directed DNA Polymerase; Resistance; Resistance development; Resveratrol; Reverse Transcriptase Inhibitors; Ribonucleotide Reductase; Sirolimus; Testing; Therapeutic; Time; Toxic effect; Variant; Viral; Viral Drug Resistance; Viral Proteins; Virion; Virus; age related; alternative treatment; analog; cellular targeting; density; drug sensitivity; env Gene Products; experience; improved; in vivo; inhibitor/antagonist; neuropsychiatry; non-nucleoside reverse transcriptase inhibitors; nucleoside analog; older patient; prevent; public health relevance; resistance mechanism; small molecule; stoichiometry; treatment strategy; viral resistance; virus envelope

DESCRIPTION (provided by applicant): Highly active antiretroviral therapy (HAART) has dramatically increased life expectancy in HIV infection and by 2015 more than half of HIV patients in the U.S. will be older than 50. Elderly HIV patients often experience comorbidities such as neuropsychiatric complications and heart, kidney and liver disease, which require additional medications. For those patients failing HAART due to HIV drug resistance, the recently developed antiretroviral class of CCR5 antagonists represents an alternative treatment option. Maraviroc is currently approved for patients infected with drug-resistant HIV viruses that use CCR5 as a coreceptor (the so-called R5 strains) and Vicriviroc is in Phase III clinical trials. Importantly, CCR5 antagonists, unlike HIV non-nucleoside reverse transcriptase and protease inhibitors, neither induce nor inhibit cytochrome P450 3A4, which is responsible for the metabolism of many medications commonly used by the elderly. Thus, CCR5 antagonists may provide safer treatment options for elderly patients with drug-resistant R5 HIV infection because of the reduced potential for drug interaction with coadministered medications. However, recent clinical trials demonstrate that R5 HIV can develop resistance to CCR5 antagonists. Viruses resistant to CCR5 antagonists often gain the ability to use antagonist-bound CCR5, which is manifested by incomplete viral inhibition (plateau at <100%) in drug susceptibility assays. In Preliminary Results we demonstrate that these inhibition plateaus are affected by CCR5 density, with increased viral suppression achieved at lower CCR5 densities. These results provide the first indication that decreasing CCR5 can control viral resistance to CCR5 antagonists. Our long-term goal is to control HIV drug-resistance by targeting cellular components required in the HIV life cycle. The objective of this proposal is to determine the mechanism by which R5 HIV resistant to CCR5 antagonist regains sensitivity at reduced CCR5 density. Our hypothesis is that R5 HIV resistant to CCR5 antagonist regains sensitivity at reduced CCR5 density because the affinity of the resistant virus envelope protein is lower for antagonist-bound CCR5 than for free CCR5. We have one Specific Aim: To determine the affinity of CCR5 antagonist-resistant gp120 for free and bound-CCR5, the length of the lag phase for association of CD4 and CCR5 (free and antagonist-bound) and the stoichiometry (number of antagonist-bound CCR5 molecules engaged per virion) in CCR5 antagonist-resistant R5 HIV infection. We will determine the affinity of resistant gp120 for free and bound-CCR5 by binding assays, the length of the lag phase for association of CD4 and CCR5 (free and antagonist-bound) in pseudovirus infections and cell-cell fusion assays, and the stoichiometry in pseudovirus infection of cell lines with varying CCR5 densities. Successful proof of this hypothesis will suggest CCR5 internalization (i.e., using RANTES analogs) and inhibition of expression (i.e., using RNA interference) as potential therapeutic strategies to restore sensitivity to CCR5 antagonists and thus improve quality of live for HIV patients, especially for the elderly. PUBLIC HEALTH RELEVANCE: According to the 2007 Workshop on HIV Infection and Aging, organized among others by the NIAID and the NIA, "identification of particular antiretroviral drugs or treatment strategies that may be more effective in older HIV-infected individuals is essential". For elderly HIV patients failing HIV treatment due to viral drug resistance, the newly developed CCR5 antagonists represent an attractive treatment option because they are active against drug-resistant HIV and because they have reduced potential for toxicity. Since HIV can develop resistance to CCR5 antagonists, we will identify the mechanism of drug resistance and potential strategies for its control, which will improve quality of life for patients with drug resistant HIV, especially for the elderly.

描述（由申请人提供）：高度活跃的抗逆转录病毒疗法（HAART）大大提高了HIV感染中的预期寿命，到2015年，美国一半以上的HIV患者将年龄在50岁以上。老年HIV患者经常经历合并症，例如神经精神上的复杂性，以及需要其他药物，这需要其他药物。对于那些因HIV耐药性而导致HAART失败的患者，最近开发的CCR5拮抗剂的抗逆转录病毒类是另一种治疗选择。 Maraviroc目前已批准使用使用CCR5作为共肽（所谓的R5菌株）的患者感染的患者，并且Vicriviroc正在III期临床试验中。重要的是，与HIV非核苷逆转录酶和蛋白酶抑制剂不同，CCR5拮抗剂既不会诱导也不抑制细胞色素P450 3A4，这是老年人常用的许多药物的代谢。因此，CCR5拮抗剂可以为耐药R5 HIV感染的老年患者提供更安全的治疗选择，因为与共同药物相互作用的潜力降低了。但是，最近的临床试验表明，R5 HIV可以对CCR5拮抗剂产生抗性。抗CCR5拮抗剂的病毒通常会获得使用拮抗剂结合的CCR5的能力，这在药物敏感性测定中表现出了不完全的病毒抑制（平稳性<100％）。在初步结果中，我们证明了这些抑制高原受CCR5密度的影响，在较低的CCR5密度下，病毒抑制增加。这些结果提供了第一个迹象，即减少CCR5可以控制对CCR5拮抗剂的病毒抗性。我们的长期目标是通过靶向HIV生命周期中所需的细胞成分来控制抗HIV药物的抗性。该提案的目的是确定R5 HIV对CCR5拮抗剂具有抗CCR5拮抗剂的机制，以降低CCR5密度。我们的假设是，R5 HIV对CCR5拮抗剂的抗性在降低的CCR5密度下恢复了敏感性，因为抗拮抗剂CCR5的抗性病毒包膜蛋白的亲和力低于自由CCR5。 We have one Specific Aim: To determine the affinity of CCR5 antagonist-resistant gp120 for free and bound-CCR5, the length of the lag phase for association of CD4 and CCR5 (free and antagonist-bound) and the stoichiometry (number of antagonist-bound CCR5 molecules engaged per virion) in CCR5 antagonist-resistant R5 HIV infection.我们将通过结合测定法确定耐药性GP120对PSEUDOVIRUS感染中CD4和CCR5（自由和拮抗剂结合）的滞后阶段的长度以及细胞细胞融合测定的滞后阶段的长度，以及在pSeudovirus感染中具有vareing ccr5 ccr5 sensities的细胞感染。该假设的成功证明将表明CCR5内在化（即使用RANTES类似物）和表达抑制（即使用RNA干扰）是恢复对CCR5拮抗剂敏感性的潜在治疗策略，从而提高了HIV患者的LIVE质量，尤其是对老年人的敏感性。公共卫生相关性：根据2007年关于艾滋病毒感染和衰老的研讨会，由NIAID和NIA组织，“鉴定了可能在年龄较大的HIV感染者中更有效的特定抗逆转录病毒药物或治疗策略是必不可少的”。对于因病毒耐药性而导致的HIV治疗失败的老年HIV患者，新开发的CCR5拮抗剂代表了一种有吸引力的治疗选择，因为他们对耐药性HIV具有活跃性，并且由于毒性的潜力降低了。由于HIV可以对CCR5拮抗剂产生抵抗力，因此我们将确定耐药性和潜在策略的控制机制，这将改善耐药HIV患者的生活质量，尤其是对于老年人。