HIV-1 R5 envelope determinants and properties that affect transmission

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 ccr5和R5毒株的异性传播引起的。然而，在传播过程中存在一个严格的瓶颈，因此在大约80%的感染中只传播一种病毒变体。目前尚不清楚传播的病毒是否比不传播的病毒具有优势。然而，R5包膜在不同的特性上差异很大，这些特性可能对HIV-1的传播产生强烈影响。这些特性包括：(1)巨噬细胞趋向性；(2)通过低水平CCR5感染细胞的能力；(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的优势。我们提出以下目标。目的1：研究传播的方正/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分支B和C的三个属性。我们将包括急性感染阶段的envs，包括密切代表传播菌株的方正信封。我们将与后期疾病阶段的R5包膜进行比较，这些包膜涵盖了待研究特性的广泛变化。因此，Aim 1实验将揭示传播的方正/急性信封是否形成具有特定属性集的不同子集。目的2：评估方正/急性或其他具有特定特性的R5包膜是否赋予朗格罕细胞或宫颈外植体培养作为男性向女性传播模型的增强倾向：我们将研究R5方正/急性包膜以及覆盖目的1中记录的变异的后期疾病阶段包膜。这些包膜将测试不同DC（包括lc）和子宫颈外植体培养物的感染，并研究通过DC的t细胞的交叉感染。总之，这些实验将有助于阐明不同的环境特性如何影响传播。目的3：鉴定子宫颈外植体培养有效感染的包膜决定因素：我们将绘制子宫颈外植体培养有效感染的包膜决定因素。我们的建议将首次全面研究不同进化枝的R5 envs的特性变化如何影响它们感染不同DC亚群和外植体培养的能力，并将其作为男性到女性传播的模型。重要的是，我们将确定赋予有效传播的环境特性和决定因素。获得的数据将提供有关传播机制的新见解，并有助于确定可以被杀微生物剂和疫苗靶向的传播膜中的漏洞。

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. PUBLIC HEALTH RELEVANCE: Our application proposes an extensive investigation into the biological properties of HIV-1 viruses that are transmitted. We will use infection of vaginal and cervical cultures as a model of sexual transmission to evaluate which HIV-1 characteristics confer the most efficient infection. Identification of the viral properties and determinants that confer infection of such cultures will provide new insights into the mechanisms of transmission. Our data will help identify vulnerabilities of transmitting viruses that can be targeted by microbicides and vaccines designed to elicit protection against global HIV-1.