Elucidating the role of B cell mediated trans infection in the establishment of the latent HIV-1 reservoir

阐明 B 细胞介导的反式感染在潜伏 HIV-1 病毒库建立中的作用

• 批准号: 10675438
• 负责人: NICOLAS PAUL SLUIS-CREMER
• 金额: $ 72.85万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-02 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10675438
• 关键词: Address; Alleles; Antigen-Presenting Cells; B-Cell Activation; B-Lymphocytes; BLT mice; Blood; C-Type Lectins; CCR5 gene; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell Separation; Cell physiology; Cells; Cholesterol Homeostasis; DNA; Data; Dendritic Cells; Genetic; Goals; HIV; HIV-1; Helper-Inducer T-Lymphocyte; In Vitro; Individual; Infection; Knowledge; Lymphoid Tissue; MHC Class I Genes; Macrophage; Mediating; Pathogenesis; Phenotype; Play; Proliferating; Reporting; Resistance; Rest; Role; T-Lymphocyte Subsets; Viral Pathogenesis; Viral reservoir; Viremia; Virus Latency; Withdrawal; antiretroviral therapy; cell type; experimental study; humanized mouse; in vivo; insight; latent HIV reservoir; novel; particle; peripheral blood; secondary lymphoid organ; single cell analysis; trait; transmission process; viral rebound; viral transmission

SUMMARY HIV-1 can proliferate through both the release of cell-free particles (cis-infection) and by cell-to-cell transmission (trans-infection). Prior studies have shown that HIV-1 trans-infection: (i) is significantly more efficient than cis-infection; (ii) can efficiently infect resting CD4+ T cells, which are inherently resistant to cis- infection; and (iii) is largely insensitive to inhibition by antiretroviral therapy (ART). Consequently, HIV-1 trans- infection is thought to play a key role in the pathogenesis of HIV-1 infection. Direct evidence of HIV-1 trans- infection in vivo, however, is lacking! Our group was the first to demonstrate that activated B cells express the C-type lectin DC-SIGN and have the ability to sequester and then efficiently transfer HIV-1 to bystander CD4+T cells. B cells have a greater capacity to transfer HIV-1 to CD4+ T cells than other antigen presenting cells, including dendritic cells (DCs) and macrophages. We recently found that B cells, but not immature or mature DC, also have the unique ability to efficiently trans-infect CD4+ naïve (TN) cells – which do not express the CCR5 receptor – with R5-tropic HIV-1. Importantly, we have reported that B cells from HIV-infected nonprogressors (NPs, individuals who control viremia in the absence of ART) do not support HIV-1 trans- infection of CD4+ T cells. Consistent with these findings, purified CD4+ TN cells isolated from NPs harbor a very small (or even negligible) reservoir of total HIV-1 DNA, compared to ART-treated progressors. In this R01 application, our overarching hypothesis is that B lymphocyte-mediated cell-to-cell HIV-1 trans-infection contributes to the establishment and replenishment of the latent viral reservoir in resting CD4+ T cells, in particular CD4+ TN and T follicular helper cells. We propose to use novel state-of the-art approaches to investigate this hypothesis, and expect to provide the first evidence that HIV-1 trans-infection plays a key role in viral pathogenesis.

总结 HIV-1可以通过释放无细胞颗粒（顺式感染）和通过细胞与细胞之间的相互作用来增殖。 传播（transinfection）。先前的研究表明，HIV-1的跨感染：（i）明显高于 比顺式感染更有效;（ii）可以有效地感染静息的CD 4 + T细胞，这些细胞固有地对顺式感染具有抗性。 感染;和（iii）很大程度上对抗逆转录病毒疗法（ART）的抑制不敏感。因此，HIV-1反式- 感染被认为在HIV-1感染的发病机制中起关键作用。HIV-1反式病毒的直接证据 然而，缺乏体内感染！我们的小组是第一个证明活化的B细胞表达 C型凝集素DC-SIGN具有隔离HIV-1并将其有效转移给旁观者的能力 CD 4 +T细胞。B细胞比其他抗原呈递细胞具有更大的将HIV-1转移到CD 4 + T细胞的能力 细胞，包括树突状细胞（DC）和巨噬细胞。我们最近发现，B细胞，但不是不成熟或 成熟的DC也具有有效地反式感染CD 4+幼稚（TN）细胞的独特能力，所述TN细胞不表达 CCR 5受体-与R5嗜性HIV-1。重要的是，我们已经报道了来自HIV感染者的B细胞 非进展者（NP，在没有ART的情况下控制病毒血症的个体）不支持HIV-1转基因， 感染CD 4 + T细胞。与这些发现一致，从NPs中分离的纯化的CD 4 + TN细胞具有 与ART治疗的进展者相比，HIV-1总DNA的储存量非常小（甚至可以忽略不计）。在此R 01 应用中，我们的首要假设是B淋巴细胞介导的细胞间HIV-1反式感染 有助于在静息的CD 4 + T细胞中建立和补充潜伏病毒库， 特别是CD 4 + TN和T滤泡辅助细胞。我们建议使用新的最先进的方法， 研究这一假设，并期望提供第一个证据表明，HIV-1的反式感染发挥了关键作用， 病毒发病机制。