TOWARDS A MORE RELEVANT MODEL OF HIV INFECTION

建立更相关的 HIV 感染模型

• 批准号: 9526462
• 负责人: JULIE M. OVERBAUGH
• 金额: $ 88万
• 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/9526462
• 关键词: Area; Benchmarking; CD4 Antigens; Cell Culture Techniques; Cells; Chimera organism; Evaluation; Gatekeeping; HIV; HIV Infections; HIV-1; HIV-1 vaccine; Human; Infection; Injecting drug user; Interferons; Intervention; Macaca; Mediating; Methods; Modeling; Pathogenesis; Pathogenicity; 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; public health relevance; 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：描述：为临床前HIV-1研究提供了重要的基准，作为推进疫苗和复兴方法的守门人。忠实地，Thel概括了HIV-1传播的关键特征和迄今为止人类的发病机理。 - 适应HIV-1的变体。移动最佳的RD，这是一种生成致病性的过程，包括猕猴中病毒的序列化。大流行。我们发现了针对人类循环的传播/创始人（T/f）的病毒的几个障碍。选择HIV-1个变体。 在我们的初步研究中，我们发现IFN刺激的反应具有猕猴T细胞中循环T/f exult的SHIV的明显，但在适应性的shive中没有其他关键的特异性障碍。通常，这是一个较差的T/ F变体的受体，可以根据实验室适应的HIV-1变异来解释偏差，而T/ F变体可以适应猕猴CD4受体，适应导致抗原变化。改变对HIV-1疫苗预防的核心的几个宽NAB的识别。该模型的实用性将途径开发出具有理性设计的SHIV，并具有增强的HIV-1疫苗临床前研究和预防方法的效用。