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B-1 B cell responses to oligomannosyl antigens of HIV-1

B-1 B 细胞对 HIV-1 寡甘露糖基抗原的反应

基本信息

批准号：
9078722
负责人：
DENONG WANG
金额：
$ 88.36万
依托单位：
SRI INTERNATIONAL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-02 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9078722
关键词：
Acquired Immunodeficiency Syndrome Antibodies Antibody Response Antigens Area Attention Autoantibodies Autoantigens B cell repertoire B-Lymphocyte Subsets B-Lymphocytes Binding Binding Sites Blood Circulation CD19 gene Carbohydrates Cerebrospinal Fluid Characteristics Clone Cells Development Epidemic Epitopes Experimental Autoimmune Encephalomyelitis Glycoproteins Goals Greater sac of peritoneum HIV HIV Antibodies HIV Antigens HIV Envelope Protein gp120 HIV Infections HIV vaccine HIV-1 Human Immune response Immune system Immunity Immunization Immunoglobulins Individual Investigation Keyhole Limpet Hemocyanin Laboratories Lead Lymphocyte Malignant neoplasm of prostate Masks Mediating Modeling Molecular Molecular Profiling Multiple Sclerosis Mus Normal Cell PTPRC gene Patients Play Polysaccharides Population Preventive Production Public Health Research Personnel Role SJL/J Mouse Sequence Analysis Serological Serum Technology Time Vaccines Viral Vaccines Virion Work base cell mediated immune response comparative deep sequencing human subject immunogenic in vivo interest men neutralizing antibody nonhuman primate novel progenitor public health relevance response sugar therapeutic vaccine vaccine development vaccine response vaccine trial

项目摘要

DESCRIPTION (provided by applicant): The antibody response to HIV-1 that is mediated by B-1 B cells is a largely unexplored area in HIV vaccine development. However, recent progress has raised important questions about whether the conventional B-2 B cell-oriented immunization strategies are solely responsible for induction of HIV-1 broadly neutralizing antibodies (bnAbs), [including those that are highly specific for carbohydrate epitopes and those that are characteristically polyreactive and autoreactive, as these antibodies are often seen in the B-1 repertoire.] Importantly, such antibodies represent dominant classes of HIV-1 bnAbs identified from a portion of HIV-infected subjects using the advanced technologies of single-cell cloning and deep sequencing. Our team has been studying carbohydrate antigens and anti-carbohydrate B cell responses for years. Recently, we obtained evidence that oligomannose-based HIV antigens are immunogenic in vivo under certain conditions. In essence, we observed that autoantibodies targeting Man9 clusters were significantly increased in the blood circulation of men with aggressive prostate cancer, in the cerebrospinal fluid of patients with multiple sclerosis, and in the serum of mice with experimental autoimmune encephalomyelitis (EAE). Interestingly, co- immunization of SJL/J mice with a Man9-KLH conjugate at the time of EAE induction elicited highly significant levels of anti-Man9-cluster autoantibodies. These anti-sera are strongly cross-reactive with HIV-1 gp120 glycoproteins (see Preliminary Results). Moreover, we discovered that immunization of non-human primates (NHP) using human RV144 HIV vaccines elicited significant levels of antibody responses to broadly HIV- neutralizing glyco-epitopes, including oligomannoses and other N-glycan cryptic antigens (Preliminary Results). Most importantly, we recently uncovered a significant population of oligomannose (Man9) cluster-binding B cells (BMan9+) in the naive B cell repertoire that are readily reactive with oligomannose clusters. These B cells represent approximately 12% of CD19+CD45+ B cells in the blood circulation of healthy human subjects. Interestingly, the BMan9+ B cell population is also present in mice, constituting approximately 10% of B-1a (CD19+CD5+) and 2% of B-1b (CD19+CD5-) B cells in the peritoneal cavity. Given that B-1 and B-2 B cells differ significantly in responding to an antigenic stimulation and that most HIV-1 vaccine strategies were developed based on B-2 responses without consideration of the B-1 potential, we propose to conduct a focused investigation of the B-1 B cell-mediated antibody responses to HIV-1. [In essence, we will apply a key HIV vaccine, RV144, to probe the B-1/ BMan9+ B cell responses in multiple species, including human, NHP, IgH-allotype chimeric mice, and humanized mice. Specifically, we will examine whether human RV144 vaccine elicited the characteristic profile of anti-carbohydrate antibody responses as observed in NHP models (Aim 1); examine contributions of murine B-1 and B-2 B cells to production of anti-HIV-1 antibodies in responding to RV144 vaccines (Aim 2); determine whether the human BMan9+ B cells in humanized mice contribute to anti-oligomannose responses and other anti-HIV antibody responses (Aim 3); and explore potential molecular signatures of B-1/BMan9+ B cell-mediated anti-carbohydrate antibody responses by a comparative IgV region sequence analysis (Aim 4).] [In summary, this revised R01 application focuses on identification of molecular and cellular signatures of the B-1/BMan9+ B cell-mediated immune responses to HIV-1 and exploration of the potential of this newly recognized B cell subset in human HIV vaccine development. If successful, this project could lead to the strategic development of novel preventive and/or therapeutic vaccine strategies against HIV infection and AIDS.]

描述（由申请方提供）：由B-1 B细胞介导的HIV-1抗体应答是HIV疫苗开发中一个尚未探索的领域。然而，最近的进展提出了重要的问题，即传统的B-2 B细胞导向的免疫策略是否仅负责诱导HIV-1广泛中和抗体（bnAb），[包括那些对碳水化合物表位高度特异性的抗体和那些特征性多反应性和自身反应性的抗体，因为这些抗体通常在B-1库中可见。]重要的是，这些抗体代表了使用单细胞克隆和深度测序的先进技术从一部分HIV感染受试者中鉴定出的HIV-1 bnAb的主要类别。我们的团队多年来一直在研究碳水化合物抗原和抗碳水化合物B细胞反应。最近，我们获得的证据表明，寡甘露糖为基础的HIV抗原在体内免疫原性在某些条件下。从本质上讲，我们观察到靶向Man 9簇的自身抗体在患有侵袭性前列腺癌的男性的血液循环中、在患有多发性硬化症的患者的脑脊液中以及在患有实验性自身免疫性脑脊髓炎（EAE）的小鼠的血清中显著增加。有趣的是，在EAE诱导时用Man 9-KLH缀合物共免疫SJL/J小鼠引起高度显著水平的抗Man 9簇自身抗体。这些抗血清与HIV-1 gp 120糖蛋白具有强烈的交叉反应性（见初步结果）。此外，我们发现使用人RV 144 HIV疫苗免疫非人灵长类动物（NHP）引起了对广泛HIV中和糖表位（包括寡甘露糖和其他N-聚糖隐蔽抗原）的显著水平的抗体应答（初步结果）。最重要的是，我们最近发现了在幼稚B细胞库中大量的低聚甘露糖（Man 9）簇结合B细胞（BMan 9+），其容易与低聚甘露糖簇反应。这些B细胞代表健康人受试者血液循环中约12%的CD 19 + CD 45 + B细胞。有趣的是，BMan 9 + B细胞群也存在于小鼠中，在腹腔中约占B-1a（CD 19 + CD 5+）的10%和B-1 B（CD 19 + CD 5-）B细胞的2%。考虑到B-1和B-2 B细胞对抗原刺激的反应显著不同，并且大多数HIV-1疫苗策略是基于B-2反应而开发的，而没有考虑B-1的潜力，我们建议对B-1 B细胞介导的HIV-1抗体反应进行重点研究。[In实质上，我们将应用关键的HIV疫苗RV 144来探测多个物种中的B-1/BMan 9 + B细胞应答，包括人、NHP、IgH同种异型嵌合小鼠和人源化小鼠。具体而言，我们将检查人RV 144疫苗是否引发如在NHP模型中观察到的抗碳水化合物抗体应答的特征性概况（目的1）;检查鼠B-1和B-2 B细胞在应答RV 144疫苗时对产生抗HIV-1抗体的贡献（目的2）;确定人源化小鼠中的人BMan 9 + B细胞是否有助于抗寡聚甘露糖应答和其它抗HIV抗体应答（目的3）;并通过比较IgV区序列分析探索B-1/BMan 9 + B细胞介导的抗碳水化合物抗体应答的潜在分子特征（目的4）]。 [In总之，该修订的R 01申请集中于鉴定B-1/BMan 9 + B细胞介导的对HIV-1的免疫应答的分子和细胞特征，并探索这种新认识的B细胞亚群在人类HIV疫苗开发中的潜力。如果成功，该项目可能导致针对艾滋病毒感染和艾滋病的新型预防和/或治疗疫苗战略的战略发展。