Exploring in vitro and in vivo T cell immunity to SIV with MHC-identical macaques

利用 MHC 相同的猕猴探索体外和体内 T 细胞对 SIV 的免疫

• 批准号: 8263801
• 负责人: David H. O'Connor
• 金额: $ 49.95万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8263801
• 关键词: Acute; Adoptive Cell Transfers; Adoptive Transfer; Alleles; Allogenic; CD8B1 gene; Cell Count; Cells; Clinical Trials; Development; Epitopes; Future; HIV; Haplotypes; Health; Human; Immune response; Immunity; Immunologic Deficiency Syndromes; In Vitro; Individual; Infection; Infusion procedures; Lymphocyte; Macaca; Modeling; Nature; Population; SIV; Severities; Staging; T cell response; T-Cell Immunologic Specificity; T-Lymphocyte; Testing; Time; Vaccine Design; Vaccines; Viral; Virus Diseases; combat; in vivo; nonhuman primate; prophylactic; research study; tumor; virus genetics

DESCRIPTION (provided by applicant): Approximately 2,500,000 people were infected with human immunodeficiency virus (HIV) in 2007, underscoring the urgency of developing an effective prophylactic vaccine. The first vaccine designed to elicit CD8+ T cell responses and advance into late-stage clinical trials failed. There is thus considerable debate whether CD8+ T cells alone can protect from acquisition of HIV or reduce the severity of HIV infection. We hypothesize that CD8+ T cells directed against a single viral target, or epitope, can blunt early viral replication if present in sufficient numbers at the time of infection. In this proposal we will test this hypothesis by identifying CD8+ T cells that combat SIV and characterizing their ability to suppress viral replication in vitro. We have identified a population of macaques susceptible to simian immunodeficiency virus (SIV), the genetic cousin of HIV that tolerates infusions of CD8+ T cells derived from other macaques. If we successfully identify a suppressive CD8+ T cell specificity in the first two years of this proposal, then we will transfer massive numbers of these cells into SIV-naive macaques immediately before SIV challenge. If successful, these experiments will prove that CD8+ T cells alone can protect against SIV and support continued development of CD8+ T cell vaccines. PUBLIC HEALTH RELEVANCE: There is no definitive evidence that CD8+ T cells alone can reduce the severity of SIV infection, a primary objective of current vaccines. In this proposal we will identify a potent CD8+ T cell response that suppresses viral replication in vitro, expand these cells to massive numbers, and in- fuse the expanded T cells into macaques immediately before SIV challenge. For the first time we will be able to determine whether adoptively transferred CD8+ T cells alone can control SIV.

描述（申请人提供）：2007 年，大约有 2,500,000 人感染了人类免疫缺陷病毒 (HIV)，这凸显了开发有效预防性疫苗的紧迫性。第一种旨在引发 CD8+ T 细胞反应并进入后期临床试验的疫苗失败了。因此，单独使用 CD8+ T 细胞是否可以防止感染 HIV 或减轻 HIV 感染的严重程度存在相当大的争议。我们假设，如果感染时存在足够数量的 CD8+ T 细胞，针对单个病毒靶点或表位，可以削弱早期病毒复制。在本提案中，我们将通过鉴定对抗 SIV 的 CD8+ T 细胞并表征其在体外抑制病毒复制的能力来检验这一假设。我们已经确定了一群对猿猴免疫缺陷病毒 (SIV) 敏感的猕猴，SIV 是 HIV 的近亲，可以耐受来自其他猕猴的 CD8+ T 细胞的输注。如果我们在该提案的前两年成功识别出抑制性 CD8+ T 细胞特异性，那么我们将在 SIV 攻击之前立即将大量这些细胞转移到未接触过 SIV 的猕猴体内。如果成功，这些实验将证明仅 CD8+ T 细胞就可以预防 SIV，并支持 CD8+ T 细胞疫苗的持续开发。公共卫生相关性：没有明确的证据表明 CD8+ T 细胞单独可以降低 SIV 感染的严重程度，而这是当前疫苗的主要目标。在本提案中，我们将鉴定出一种有效的 CD8+ T 细胞反应，可在体外抑制病毒复制，将这些细胞扩增至大量，并在 SIV 攻击前立即将扩增的 T 细胞注入猕猴体内。我们将首次确定过继转移的 CD8+ T 细胞是否可以单独控制 SIV。