HIV-1 R5 envelope determinants and properties that affect transmission

描述(申请人提供)：今天，大多数新的HIV-1感染是由使用HIV-1CCR5的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%的感染中只有一个病毒变种被传播。目前尚不清楚传播的病毒是否比无法传播的病毒具有优势。然而，R5的包膜在不同的性质上有很大的差异，这可能会对HIV-1的传播产生强烈的影响。这些特性包括(1)巨噬细胞趋向性，(2)通过低水平的CCR5感染细胞的能力，以及(3)对包括趋化因子在内的CCR5配体的敏感性降低。我们的假设是，HIV-1的传播是由具有独特性质的信封授予的，这些信封赋予了传播的优势。我们提出了以下目标。目的1：为了研究传播的创始人/急性包膜是否形成一个具有特殊性质的不同子集：我们将研究HIV-1、R5、B和C两个分支的上述三种性质。我们将包括来自感染急性期的环境病毒，包括接近代表传播毒株的创始人包膜。我们将与来自疾病后期的R5包膜进行比较，这些包膜涵盖了待研究的属性的广泛变化。目标1实验因此将揭示被传递的创始人/急性包膜是否形成具有特定属性集的不同子集。目的2：评估创始/急性或其他具有特殊性质的R5包膜是否能增强郎格罕细胞或宫颈外植体培养的趋向性，作为男性向女性传播的模型：我们将研究R5创始/急性包膜以及涵盖目标1中记录的变异的疾病后期包膜。这些包膜将被检测不同DC(包括LC)和宫颈外植体培养的感染，并调查T细胞通过DC的传播。总之，这些实验将有助于阐明不同的环境属性如何影响传输。目的3：确定有效感染宫颈外植体培养的包膜决定因素：我们将定位导致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分支的R5环境蛋白特性的差异如何影响其感染不同DC亚群和宫颈外植体培养的能力，作为男性向女性传播的模型。重要的是，我们将确定赋予有效传输的环境属性和决定因素。获得的数据将为传播机制提供新的见解，并有助于识别可以成为杀菌剂和疫苗靶标的发射器包膜中的漏洞。 公共卫生相关性：我们的申请建议对传播的HIV-1病毒的生物学特性进行广泛调查。我们将使用阴道和宫颈培养的感染作为性传播的模型，以评估哪些HIV-1特征提供最有效的感染。识别病毒的特性和导致感染这些培养物的决定因素将为传播机制提供新的见解。我们的数据将有助于识别传播病毒的脆弱性，这些病毒可以成为杀菌剂和疫苗的靶标，旨在获得对全球艾滋病毒-1的保护。

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.