HIV-1 R5 envelope determinants and properties that affect transmission

HIV-1 R5 包膜决定因素和影响传播的特性

• 批准号: 8415869
• 负责人: PAUL R CLAPHAM
• 金额: $ 39.1万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-10 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8415869
• 关键词: Acute; Affect; Biological; CCR5 gene; CD4 Positive T Lymphocytes; Cells; Cervical; Characteristics; Chronic; Consensus Sequence; Data; Dendritic Cells; Disease; Event; Female; Goals; HIV-1; Heterosexuals; Infection; Investigation; Langerhans cell; Ligands; Maps; Modeling; Mutagenesis; Population; Property; Publishing; Research; Sexual Transmission; Sexually Transmitted Diseases; Staging; T-Lymphocyte; Testing; Time; Tropism; Vaccine Design; Vaccines; Vagina; Variant; Viral; Virus; cell type; chemokine; insight; macrophage; male; microbicide; penis; public health relevance; research study; restraint; transmission process

DESCRIPTION (provided by applicant): Today, the majority of new HIV-1 infections result from heterosexual transmission with HIV-1 CCR5-using, R5 strains. However, there is a tight bottleneck during transmission so that only a single virus variant is transmitted in about 80% of infections. It is not known whether the transmitted viruses carry an advantage over strains that fail to transmit. However, R5 envelopes vary extensively in different properties that are likely to have a strong impact on HIV-1 transmission. These properties include (1) macrophage-tropism, (2) capacity to infect cells via low levels of CCR5 and (3) decreased sensitivity to CCR5 ligands including chemokines. Our hypothesis is that HIV-1 transmission is conferred by envelopes with distinct properties that confer an advantage for transmission. We propose the following aims. Aim 1: To investigate whether transmitted founder/acute envelopes form a distinct subset with particular properties: We will investigate HIV-1 R5 clade B and C envs for the three properties described above. We will include envs from the acute stage of infection including founder envelopes that closely represent transmitted strains. We will compare with R5 envelopes from later disease stages that cover the wide variation in the properties to be investigated. Aim 1 experiments will thus reveal whether transmitted founder/acute envelopes form a distinct subset with a particular set of properties. Aim 2: To evaluate whether founder/acute or other R5 envelopes with specific properties confer an enhanced tropism for Langerhan's cells or ectocervical explant cultures as a model for male-to-female transmission: We will investigate the R5 founder/acute envelopes as well as later disease stage envelopes that cover the variation documented in aim 1. These envelopes will be tested for infection of different DC (including LCs) and ectocervical explant cultures and investigated for trans-infection of T-cells via DCs. Together, these experiments will help elucidate how different env properties impact on transmission. Aim 3: To identify the envelope determinants that confer efficient infection of ectocervical explant cultures: We will map envelope determinants that confer efficient infection of ectocervical explant cultures. Our proposal will provide the first comprehensive study of how variation in the properties of R5 envs of different clades impacts on their capacity to infect different DC subsets and ectocervical explant cultures as a model for male-to-female transmission. Importantly, we will identify env properties and determinants that confer efficient transmission. The data obtained will provide new insights into the mechanisms of transmission and help identify vulnerabilities in transmitter envelopes that can be targeted by microbicides and vaccines.

描述（由申请人提供）：今天，大多数新的HIV-1感染是由使用HIV-1 CCR 5的R5毒株的异性传播引起的。然而，在传播过程中存在严格的瓶颈，因此在约80%的感染中仅传播单一病毒变体。目前还不知道传播的病毒是否比不能传播的病毒株具有优势。然而，R5信封在不同的属性上差异很大，可能对HIV-1传播产生强烈影响。这些特性包括（1）嗜巨噬细胞性，（2）通过低水平的CCR 5感染细胞的能力和（3）对CCR 5配体（包括趋化因子）的敏感性降低。我们的假设是，HIV-1的传播是由具有独特特性的信封赋予的，这些信封赋予了传播的优势。我们提出以下目标。目标1：为了研究传播的创始者/急性包膜是否形成具有特定性质的不同子集：我们将研究HIV-1 R5进化枝B和C包膜的上述三种性质。我们将包括感染急性期的Env，包括密切代表传播菌株的创始人包膜。我们将与来自后期疾病阶段的R5包络进行比较，所述后期疾病阶段涵盖待研究的性质的广泛变化。因此，目标1实验将揭示传输的创始人/急性信封是否形成具有特定属性集的不同子集。目标二：为了评价具有特定性质的创始者/急性或其他R5包膜是否赋予郎格罕细胞或宫颈外外植体培养物作为男性至女性传播模型的增强的向性：我们将研究R5创始者/急性包膜以及涵盖目标1中记录的变化的后期疾病阶段包膜。将检测这些包膜对不同DC（包括LC）和宫颈外植块培养物的感染，并研究T细胞通过DC的转感染。 总之，这些实验将有助于阐明不同的env属性如何影响传输。目标3：为了确定赋予宫颈外植块培养物有效感染的包膜决定因素：我们将绘制赋予宫颈外植块培养物有效感染的包膜决定因素。 我们的建议将提供第一个全面的研究，如何在不同的分支R5 envs的属性的变化，影响他们的能力，感染不同的DC亚群和宫颈外外植体培养作为一个模型，男性到女性的传播。重要的是，我们将确定赋予有效传输的env属性和决定因素。所获得的数据将为传播机制提供新的见解，并有助于确定杀微生物剂和疫苗可以针对的发射器信封中的漏洞。