TOWARDS A MORE RELEVANT MODEL OF HIV INFECTION

建立更相关的 HIV 感染模型

• 批准号: 9144750
• 负责人: JULIE M. OVERBAUGH
• 金额: $ 87.12万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9144750
• 关键词: Area; Benchmarking; CD4 Antigens; Cell Culture Techniques; Cells; Chimera organism; Evaluation; Gatekeeping; HIV; HIV Infections; HIV-1; HIV-1 vaccine; Health; Human; Infection; Injecting drug user; Interferons; Intervention; Macaca; Mediating; Methods; Modeling; Pathogenesis; Pathway interactions; Pre-Clinical Model; Prevention; Prevention approach; Process; Research; Serial Passage; Series; T-Lymphocyte; Testing; Vaccines; Variant; Virus; base; design; fitness; pandemic disease; pre-clinical; preclinical study; receptor; response; simian human immunodeficiency virus; transmission process

 DESCRIPTION: SHIV macaque models provide an important benchmark for pre-clinical HIV-1 research, serving as a gatekeeper for advancing vaccine and other prevention approaches. The ability of such models to predict intervention(s) that will be efficacious in humans depends to a large extent on how faithfully the model recapitulates key features of HIV-1 transmission and pathogenesis in humans, including both sexual and parenteral transmission. To date, SHIVs have largely been selected by trial and error using the most readily available HIV-1 variants, often those that have been adapted to replication in cell culture (lab-adapted HIV-1 variants). As a result, few SHIV models incorporate key features of circulating variants that are the target of vaccine and other prevention methods. Although efforts in this area are increasing, approaches nonetheless generally rely on constructing and testing a series of SHIV chimeras encoding available HIV-1 variants and moving forward the one that replicates best. Of note, this process of generating pathogenic SHIVs includes serial passage of the virus in macaques to further increase replication fitness, and all of the SHIVs in current use have been adapted in this manner (adapted SHIVs). We propose to pioneer a rational design approach to developing relevant SHIVs that better represent circulating HIV-1 variants central to the pandemic. We have found several barriers to HIV-1 replication in macaque cells that are specific to transmitted/founder (T/F) viruses circulating in humans. These restrictions do not appear to be the result of known restriction factors, which are generally not specific to select HIV-1 variants. In our preliminary studies, we found that IFN-stimulated responses have a pronounced effect on the replication of SHIVs encoding circulating T/F envelope variants in macaque T cells, but not on adapted SHIVs. Another critical species-specific barrier of HIV-1s circulating in humans is the macaque CD4 receptor, which is generally a poor receptor for T/F variants, but a functional receptor for lab-adapted variants, potentially explaining the bias towards developing SHIVs based on lab-adapted HIV-1 variants. While T/F variants can be adapted to use the macaque CD4 receptor, adaptation leads to antigenic changes that alter recognition of several broad NAbs that are currently the centerpiece of HIV-1 vaccine efforts. Here, we propose to exploit these preliminary findings to define the mechanisms underlying the envelope-mediated restrictions to HIV-1 replication in macaques, to define the consequences of these changes for the utility of the model and to identify pathways to developing rationally designed SHIVs with enhanced utility for preclinical studies of HIV-1 vaccine and prevention methods.

 描述：Shiv猕猴模型为临床前HIV-1研究提供了重要的基准，可作为推进疫苗和其他预防方法的守门人。这种模型预测将在人类中有效的干预措施的能力在很大程度上取决于该模型如何忠实地概括了人类中HIV-1传播和发病机理的关键特征，包括性和父母传播。迄今为止，使用最容易获得的HIV-1变体选择了SHIV，通常是通过反复试验选择的，通常是在细胞培养（实验室适应的HIV-1变体）中适应复制的SHIV。结果，很少有SHIV模型包含循环变体的关键特征，这些变体是疫苗和其他预防方法的靶标。尽管这一领域的努力在增加，但方法尽管如此，方法通常依赖于构建和测试一系列编码可用的HIV-1变体的SHIV Chimeras，并推进重复最佳的一种。值得注意的是，这种生成致病性湿气的过程包括猕猴中病毒的系列通过，以进一步增加复制适应度，并且目前使用中的所有SHIV都以这种方式进行了调整（改编后的Shivs）。我们建议开拓一种合理的设计方法来开发相关的湿暴，以更好地代表大流行中心的循环HIV-1变体。我们发现了猕猴细胞中HIV-1复制的几个障碍，这些障碍特定于人类循环的传播/创始人（T/F）病毒。这些限制似乎不是已知限制因素的结果，这些因素通常不是选择HIV-1变体的特定因素。 在我们的初步研究中，我们发现IFN刺激的响应对猕猴T细胞中编码循环T/F包膜变体的SHIV的复制具有明显的影响，但对改编的Shivs没有。 Another critical species-specific barrier of HIV-1s circulating in humans is the macaque CD4 receptor, which is generally a poor receptor for T/F variants, but a functional receptor for lab-adapted variants, potentially explaining the bias While T/F variants can be adapted to use the macaque CD4 receptor, adaptation leads to antigenic changes that alter recognition of several broad NAbs that are currently the centerpiece HIV-1疫苗的工作。在这里，我们建议探索这些初步发现，以定义猕猴中包膜介导的HIV-1复制限制的基础机制，以确定这些变化对模型实用性的影响，并确定开发HIV-1疫苗和预测方法增强实用性的合理设计的SHIV的途径。