HIV-1 Evolution and Functional Correlates of MTCT

HIV-1 进化和 MTCT 功能相关性

• 批准号: 8423676
• 负责人: Edward N Janoff
• 金额: $ 75.39万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-09 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8423676
• 关键词: Active Immunization; Acute; Address; Adult; Anatomy; Antibodies; Autologous; Biological Assay; Biology; Blood; Breast Feeding; CCR5 gene; CD4 Positive T Lymphocytes; Cell Line; Cells; Cellular Tropism; Characteristics; Child; Chromosome Mapping; Chronic; Data; Development; Evolution; Exhibits; Frequencies; Genes; Genetic; Genetic Variation; Genome; HIV; HIV-1; Immune; Immune response; Infant; Infection; Kinetics; Length; Modeling; Molecular; Monoclonal Antibodies; Mothers; Passive Immunization; Phenotype; Phylogenetic Analysis; Plasma; Property; RNA; Random Allocation; Relative (related person); Resistance; Role; Sampling; Serum; Structure; Time; Tropism; Umbilical Cord Blood; Variant; Viral; Virus; Woman; Work; base; cohort; cytokine; deep sequencing; env Gene Products; improved; in vivo; inhibitor/antagonist; macrophage; neutralizing antibody; postnatal; pressure; prevent; pyrosequencing; receptor; transmission process

DESCRIPTION (provided by applicant): Mucosal transmission of HIV involves a strong bottleneck effect and most often, a single founder virus is transmitted. The relative contributions of stochastic (random) selection vs. active selection by specific viral and host characteristics to this bottleneck are unclear. Mother-to-child HIV-1 transmission (MTCT) through breastfeeding, in which transmission pairs and timing of infant infection are readily identified, provides an instructive model to address these important and unresolved questions. We will use serial samples from a large, well characterized cohort of HIV-1 infected Zimbabwean women who transmitted HIV-1 through breastmilk. This cohort includes women with chronic HIV-1 infection (CI; N=35), and women who acquired primary HIV-1 infection post-partum (acute infection, AI; N=13). We combine phylogenetics (with frequency analyses based on deep sequencing data) with functional assays (CD4 and co-receptor use, entry kinetics, neutralization sensitivity), to quantitatively and comprehensively analyze the relationship of founder viruses to maternal blood or breastmilk variants, quantify the relative contributions of stochastic vs. active selectio, identify selection pressures on envelope (env), differentiate when selection pressures may operate during the transmission bottleneck, and determine whether founder env variants are better adapted than other non- transmitted variants for postnatal MTCT. Delineation of the biologic properties of transmitted variants along with mapping the genetic bases of these biologic properties, should improve understanding of HIV-1 entry and the mechanisms of action of HIV-1 entry inhibitors. These studies will also improve our understanding of the in vivo selective pressures exerted by autologous neutralizing antibodies and innate factors in two distinct and relevant anatomic compartments (blood, where levels of antibodies are high, and breastmilk, where they are much lower) and the potential role of neutralization sensitivity or escape in transmission. Finally, these studies will specifically reveal whether increasing the neutralizing activity of blood or breastmilk (e.g., through passive or active immunization) or targeting other Env functional properties (tropism, infectivity) hold promise to block primary infection of women and children.

描述（由申请人提供）：HIV的粘膜传播涉及强瓶颈效应，并且通常会传播单个创始人病毒。相对贡献 随机（随机）选择与特定病毒和宿主特征的主动选择 这种瓶颈尚不清楚。通过母乳喂养，母亲到孩子的HIV-1传播（MTCT）很容易鉴定出婴儿感染的传播对和时间，提供了一个有指导的模型来解决这些重要且尚未解决的问题。我们将使用来自HIV-1感染的Zimbabwean妇女的大型，特征性良好的Zimbabwean妇女的串行样品，这些妇女通过母乳传播HIV-1。该队列包括患有慢性HIV-1感染的妇女（CI； n = 35），以及在发作后获得原发性HIV-1感染的妇女（急性感染，AI； n = 13）。我们将系统发育学（基于深度测序数据的频率分析）与功能测定（CD4和共受体使用，进入动力学，中和敏感性）相结合，以定量，全面地分析创建者病毒与孕妇血液或母乳的关系的基础选择，以量身定义的选择，以量化为主体的选择。在传输瓶颈期间运行，并确定与其他非传播变体的创建者Env变体是否更好地适应了产后MTCT。划定传播变体的生物学特性以及绘制这些生物学特性的遗传碱基的描述，应提高对HIV-1进入的理解和HIV-1进入抑制剂的作用机理。这些研究还将提高我们对两个不同且相关的解剖区室中自体中和抗体和先天因素所施加的体内选择性压力的理解（血液，抗体水平很高，胸部较低，在那里它们较低），以及中和敏感性或逃生的潜在作用。最后，这些研究将特别揭示增加血液或母乳的中和活性（例如，通过被动或主动免疫）是否有望阻止妇女和儿童的原发性感染。