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: 8790389
• 负责人: PAUL R CLAPHAM
• 金额: $ 41.1万
• 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 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8790389
• 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）：如今，大多数新的 HIV-1 感染是由使用 HIV-1 CCR5 的 R5 毒株的异性传播引起的。然而，传播过程存在严格的瓶颈，约80%的感染仅传播单一病毒变种。目前尚不清楚传播的病毒是否比无法传播的病毒株具有优势。然而，R5 包膜的不同特性差异很大，可能对 HIV-1 传播产生强烈影响。这些特性包括 (1) 巨噬细胞嗜性、(2) 通过低水平 CCR5 感染细胞的能力和 (3) 对 CCR5 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包膜赋予的，这些特性赋予了传播优势。我们提出以下目标。目标 1：调查传播的创始人/急性包膜是否形成具有特定属性的独特子集：我们将研究 HIV-1 R5 进化枝 B 和 C 环境的上述三个属性。我们将包括来自感染急性阶段的包膜，包括密切代表传播菌株的创始人包膜。我们将与疾病后期的 R5 包络进行比较，这些包络涵盖了要研究的特性的广泛变化。因此，目标 1 实验将揭示传输的创始人/急性包络是否形成具有一组特定属性的独特子集。目标 2：评估具有特定特性的创始人/急性或其他 R5 包膜是否赋予朗格汉细胞或子宫颈外植体培养物增强的趋向性，作为男性到女性传播的模型：我们将研究 R5 创始人/急性包膜以及疾病后期包膜，涵盖目标 1 中记录的变异。这些包膜将针对不同 DC（包括 LC）和宫颈外植体培养物的感染进行测试，并研究通过 DC 转染 T 细胞。 总之，这些实验将有助于阐明不同的环境特性如何影响传输。目标 3：确定赋予宫颈外植体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体培养物有效感染的包膜决定因素。 我们的提案将首次全面研究不同分支的 R5 envs 特性的变化如何影响它们感染不同 DC 子集和宫颈外植体培养物的能力，作为男性到女性传播的模型。重要的是，我们将确定环境属性和赋予有效传输的决定因素。获得的数据将为传播机制提供新的见解，并帮助识别可被杀微生物剂和疫苗瞄准的传播器包膜中的漏洞。

项目成果

HIV-1 R5 Macrophage-Tropic Envelope Glycoprotein Trimers Bind CD4 with High Affinity, while the CD4 Binding Site on Non-macrophage-tropic, T-Tropic R5 Envelopes Is Occluded.

HIV-1 R5 巨噬细胞亲性包膜糖蛋白三聚体以高亲和力结合 CD4，而非巨噬细胞亲性 T-Tropic R5 包膜上的 CD4 结合位点被封闭。

• DOI: 10.1128/jvi.00841-17
• 发表时间: 2018
• 期刊: Journal of virology
• 影响因子: 5.4
• 作者: Quitadamo,Briana;Peters,PaulJ;Repik,Alexander;O'Connell,Olivia;Mou,Zhongming;Koch,Matthew;Somasundaran,Mohan;Brody,Robin;Luzuriaga,Katherine;Wallace,Aaron;Wang,Shixia;Lu,Shan;McCauley,Sean;Luban,Jeremy;Duenas-Decamp,Maria;Go
• 通讯作者: Go

Targeted Delivery of Glucan Particle Encapsulated Gallium Nanoparticles Inhibits HIV Growth in Human Macrophages.

• DOI: 10.1155/2016/8520629
• 发表时间: 2016
• 期刊: Journal of drug delivery
• 作者: Soto ER;O'Connell O;Dikengil F;Peters PJ;Clapham PR;Ostroff GR
• 通讯作者: Ostroff GR

Ultradeep single-molecule real-time sequencing of HIV envelope reveals complete compartmentalization of highly macrophage-tropic R5 proviral variants in brain and CXCR4-using variants in immune and peripheral tissues.

• DOI: 10.1007/s13365-018-0633-5
• 发表时间: 2018-08
• 期刊: Journal of neurovirology
• 影响因子: 3.2
• 作者: Brese RL;Gonzalez-Perez MP;Koch M;O'Connell O;Luzuriaga K;Somasundaran M;Clapham PR;Dollar JJ;Nolan DJ;Rose R;Lamers SL
• 通讯作者: Lamers SL