Apobec3 and the Neutralizing Antibody Response Against Pathogenic Retroviruses

Apobec3 和针对致病性逆转录病毒的中和抗体反应

• 批准号: 7896029
• 负责人: Mario Luis Santiago
• 金额: $ 65.75万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-22 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7896029
• 关键词: 26S proteasome; Acute; Address; Alleles; Anti-Retroviral Agents; Antibodies; Antibody Formation; Antigens; Attenuated; Binding; Binding Sites; Biological Models; Biological Preservation; Biology; Blood specimen; Boxing; Cells; Chromosomes, Human, Pair 15; Complex; Data; Development; Disease; Dominant Genes; Engineering; Enzymes; Epitopes; Event; Exhibits; Friend Murine Leukemia Virus; Friends; Future; Genes; Glean; Goals; HIV Envelope Protein gp120; HIV-1; HIV-1 vaccine; Homologous Gene; Human; Humoral Immunities; Immune; Immune response; Immune system; Immunity; Immunization; Immunology; Immunotherapeutic agent; Infection; Interferons; Kinetics; Knowledge; Link; Macaca; Macaca mulatta; Maps; Mediating; Messenger RNA; Modality; Modeling; Monitor; Monkeys; Mouse Strains; Mus; Natural Immunity; Pathogenesis; Pathology; Peripheral Blood Mononuclear Cell; Phenotype; Plasma; Production; Qualifying; Recombinants; Recovery; Regulation; Research; Research Personnel; Resistance; Retroviridae; Retroviridae Infections; Reverse Transcription; SIV; Sampling; Science; Specificity; Staging; Structural Models; System; T-Lymphocyte; T-Lymphocyte Epitopes; Time; TimeLine; Upper arm; Vaccine Research; Vaccines; Variant; Viral; Viral Load result; Virion; Virus; Virus Diseases; Virus-like particle; abstracting; deoxycytidine deaminase; env Gene Products; fascinate; improved; innovation; insight; neutralizing antibody; nonhuman primate; novel; particle; prevent; response; simian human immunodeficiency virus; tool; vaccine development; vif Gene Products

ABSTRACT Despite decades of research, the immunological correlates of protection against HIV-1 infection in humans or SIV infection in nonhuman primates remain poorly understood. In contrast, studies on Friend retrovirus (FV) infection in mice highlighted the importance of the neutralizing antibody response in disease recovery and vaccine protection, a response widely considered as critical for a successful HIV-1 vaccine. Interestingly, the neutralizing antibody response in FV infection is significantly influenced by a key host gene, Rfv3. We recently identified Rfv3 as Apobec3, a potent innate restriction factor that counteracts a broad range of retroviruses including HIV-1 (Santiago ML et al. 2008. Science 321: 1343-6). This discovery revealed an unexpected link between the innate and humoral arms of the immune response that may have important implications for HIV-1 vaccine development. Our overall objective in this proposal is to probe the fascinating link between Apobec3 activity and the neutralizing antibody response against pathogenic retroviral infections in three species: mice, monkeys and humans. In Specific Aim 1, the underlying mechanism of the Apobec3/Rfv3 phenotype will be dissected in the FV murine model. This will involve in-depth studies on virus dynamics, interferon regulation and pathology in wild type versus Apobec3-deficient mice, and a detailed characterization of neutralizing antibodies against the FV envelope protein. Since the simian and human homologues of Apobec3 are thwarted by the lentiviral Vif protein, we hypothesize that attenuating Vif function may rescue Apobec3 and improve neutralizing antibody responses. In Specific Aim 2, wild type and Vif-attenuated SIV and SHIV strains will be used to infect rhesus macaques. Apobec3 function and neutralizing antibody kinetics, potency, breadth and epitope specificity will be monitored from sequential blood samples. Finally, Apobec3 function has been linked to HIV-1 resistance, but its impact on HIV-1 antibody responses remains unknown. The recent acquisition of samples from the earliest stages of HIV-1 infection therefore opens an unprecedented opportunity to link innate Apobec3 function and neutralizing antibody development. Thus, in Specific Aim 3, we propose to examine the relationship between Vif functional diversity, Apobec3 inducibility, interferon regulation, and envelope-directed antibody development in HIV-1 infection. We have assembled a highly qualified team of investigators with expertise in Apobec3/Vif biology, murine retrovirus immunology, the SIV and SHIV macaque model systems, and HIV-1 pathogenesis for this project. We postulate that understanding Apobec3-mediated innate immunity may yield promising and "outside the box" insights for augmenting neutralizing antibody responses against HIV-1 infection.

抽象的 尽管经过数十年的研究，人类或人类免受 HIV-1 感染的免疫学相关性仍然存在。 非人灵长类动物中的 SIV 感染仍知之甚少。相比之下，对 Friend 逆转录病毒（FV）的研究 小鼠感染凸显了中和抗体反应在疾病恢复中的重要性 疫苗保护，这种反应被广泛认为对于成功的 HIV-1 疫苗至关重要。有趣的是， FV 感染中的中和抗体反应受到关键宿主基因 Rfv3 的显着影响。我们最近 将 Rfv3 鉴定为 Apobec3，一种有效的先天限制因子，可抵抗多种逆转录病毒 包括 HIV-1（Santiago ML 等人，2008 年。 Science 321：1343-6）。这一发现揭示了一个意想不到的联系 先天免疫反应和体液免疫反应之间的关系可能对 HIV-1 产生重要影响 疫苗开发。我们在本提案中的总体目标是探讨 Apobec3 之间的迷人联系 三种物种中针对致病性逆转录病毒感染的活性和中和抗体反应：小鼠、 猴子和人类。在具体目标 1 中，Apobec3/Rfv3 表型的基本机制将是 在 FV 小鼠模型中进行解剖。这将涉及对病毒动力学、干扰素调控的深入研究 野生型与 Apobec3 缺陷小鼠的病理学比较，以及中和的详细表征 抗 FV 包膜蛋白的抗体。由于 Apobec3 的猿类和人类同源物受到阻碍 通过慢病毒 Vif 蛋白，我们假设减弱 Vif 功能可能会拯救 Apobec3 并 改善中和抗体反应。在特定目标 2 中，野生型和 Vif 减毒 SIV 和 SHIV 菌株将用于感染恒河猴。 Apobec3 功能和中和抗体动力学、效力、 宽度和表位特异性将从连续的血液样本中进行监测。最后，Apobec3 函数有 与 HIV-1 耐药性有关，但其对 HIV-1 抗体反应的影响仍不清楚。最近的 因此，从 HIV-1 感染的最早阶段获取样本开启了前所未有的 将先天 Apobec3 功能与中和抗体发育联系起来的机会。因此，在具体目标 3 中， 我们建议检查 Vif 功能多样性、Apobec3 诱导性、干扰素之间的关系 HIV-1 感染中的调节和包膜定向抗体的发展。我们组建了一个高度 由具有 Apobec3/Vif 生物学、鼠逆转录病毒免疫学、SIV 专业知识的合格研究团队组成 和 SHIV 猕猴模型系统，以及该项目的 HIV-1 发病机制。我们假设这种理解 Apobec3 介导的先天免疫可能会产生有希望的、“打破常规”的见解，以增强 中和针对 HIV-1 感染的抗体反应。