Protective cellular immune responses in HIV-1 discordant couples

HIV-1 不一致夫妇的保护性细胞免疫反应

• 批准号: 7678364
• 负责人: CAREY FARQUHAR
• 金额: $ 62.05万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7678364
• 关键词: Address; Antigenic Specificity; Biological Assay; CD4 Positive T Lymphocytes; CD8B1 gene; Cell physiology; Cellular Immunity; Cohort Studies; Communities; Consensus Sequence; Counseling; Couples; Data; Development; Enrollment; Epidemiologic Studies; Epitopes; Event; Evolution; Exposure to; Future; Genetic; Genital system; Genome; HIV; HIV Seropositivity; HIV-1; Heterosexuals; Human; Immune response; Immunity; Immunologics; Immunology procedure; Individual; Infant; Infection; Interferon Type II; Kenya; Laboratories; Literature; Measures; Monitor; Mothers; Nature; Peptides; Phenotype; Plasma; Play; Predisposition; Prevalence; Prevention; Process; Prospective Studies; RNA; Recruitment Activity; Reporting; Research Design; Research Personnel; Risk; Role; Sex Behavior; Site; Specificity; Specimen; Staining method; Stains; System; T-Lymphocyte; Testing; Time; Vaccine Research; Viral; Viral Load result; Viral Markers; Virus; Visit; base; cohort; cytokine; design; experience; follow-up; genital secretion; insight; interest; member; peptide A; prevent; programs; prospective; protective effect; resistance mechanism; response; sex risk; transmission process; vaccine development

DESCRIPTION (provided by applicant): Approximately 1 out of 10 couples in Kenya is HIV-1 discordant despite ongoing sexual activity that results in HIV-1 exposure for the uninfected member of the couple. Several groups have described cellular immune responses in HIV-1-exposed individuals and have suggested that these contribute to reduced susceptibility to HIV-1 infection. However, none of these studies has been able to determine whether the presence of an HIV-1-specific immune response protects against HIV-1 acquisition or is merely a marker of intermittent viral exposure. In this study, we propose to recruit a large cohort of HIV-1-discordant couples and follow both members of the couple prospectively, using HIV-1 transmission as the endpoint. For Aim 1 we will determine whether positive HIV-1-specific CD8+ interferon-gamma (IFN-gamma) responses in the HIV-1-uninfected partner are associated with protection against HIV-1 acquisition during 24 months of follow-up. Aim 2 focuses on HIV-1- specific CD4+ T helper responses and will ascertain whether these are significantly more common in non- transmitting couples compared to HIV-1 transmitting couples. In Aim 3 we will perform detailed analyses of HIV-1-specific T cell function, phenotype, and durability in a subset of 10 enrolled couples, defining viral specificity by sequencing genital and plasma HIV-1 from infected partners. A total of 600 HIV-1-discordant couples will be enrolled in this Nairobi-based study, with approximately 1/3 of couples recruited from an ongoing discordant couple study and the remaining coming from the community. At enrollment, CD8+ and CD4+ T cell responses against peptides derived from a consensus sequence clade A HIV-1 will be measured in the uninfected partner using ELISpot assays and intracellular cytokine staining. At the same visit, HIV-1-infected partners will have a baseline HIV-1 viral load and genital tract HIV-1 RNA shedding quantified using PCR. Follow-up visits will occur every 3 months for both partners and will include assessment of sexual risk behavior and rapid HIV-1 testing for the uninfected partner. During 2 years of follow-up, we estimate 54-65 (approximately 10%) couples will transmit HIV-1 despite regular HIV-1 prevention counseling. Comparing HIV-1 transmitting with non-transmitting couples will inform future vaccine research about whether such responses are associated with reductions in HIV-1 acquisition and may provide valuable insight into the nature of protective cellular immunity for future vaccine development.

描述（由申请人提供）：肯尼亚的10对夫妇中约有1名是HIV-1不一致的，尽管持续的性活动会导致这对夫妇未感染的成员HIV-1暴露。几个组描述了暴露于HIV-1的个体中的细胞免疫反应，并提出这些反应有助于降低对HIV-1感染的敏感性。但是，这些研究都无法确定HIV-1特异性免疫反应的存在是否可以防止HIV-1的获取或仅仅是间歇性病毒暴露的标志。在这项研究中，我们建议招募一大批HIV-1五杆夫妇，并以HIV-1传播为终点，并前瞻性地跟随这对夫妇的两个成员。对于AIM 1，我们将确定HIV-1未感染的伴侣中HIV-1特异性CD8+干扰素 - γ（IFN-GAMMA）反应是否与在随访的24个月内的保护HIV-1获取有关。 AIM 2专注于HIV-1-特异性CD4+ T助手响应，并将确定与HIV-1传播夫妇相比，在非传播夫妇中是否明显更为普遍。在AIM 3中，我们将对10对夫妇的子集进行HIV-1特异性T细胞功能，表型和耐用性的详细分析，从而通过对受感染伴侣进行测序生殖器和血浆HIV-1来定义病毒特异性。这项基于内罗毕的研究将总共参加600对HIV-1五夫妻夫妇，大约有1/3对来自正在进行的不一致的夫妇研究中招募的夫妇，其余的来自社区。在入学时，使用ELISPOT分析和细胞内细胞因子染色，将在未感染的伴侣中测量源自共有序列进化枝A HIV-1的肽的CD8+和CD4+ T细胞反应。在同一访问中，HIV-1感染的伴侣将具有基线HIV-1病毒载量和使用PCR定量的生殖道HIV-1 RNA脱落。双方伴侣将每3个月进行一次随访，并包括对未感染伴侣进行性风险行为的评估和快速的HIV-1测试。在2年的随访期间，我们估计尽管有常规的HIV-1预防咨询，夫妻将传递HIV-1（约10％）。将HIV-1传输与非推广夫妇进行比较，将为未来的疫苗研究提供有关此类反应是否与HIV-1获取的减少相关的疫苗研究，并可能对保护性细胞免疫的性质有价值，以实现未来的疫苗开发。