Enhanced Anti-HIV-1 Antibody Responses in African American Women Seropositive for

非洲裔美国女性血清阳性的抗 HIV-1 抗体反应增强

• 批准号: 9321403
• 负责人: Phillip Wayne Berman
• 金额: $ 56.23万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA CRUZ
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9321403
• 关键词: AIDS/HIV problem; African American; Animals; Anti-Retroviral Agents; Antibodies; Antibody Response; Antibody Specificity; Antigens; Antiviral Agents; Biological Assay; Cohort Studies; Collaborations; DNA; Data; Disease Progression; Drug abuse; Epitopes; Ethnic Origin; Exhibits; Female; Genes; Genetic; Goals; HIV; HIV Envelope Protein gp120; HIV Infections; HIV vaccine; HIV-1; Hepatitis C; Heterosexuals; Human; Immune response; Immunization; Immunologics; Individual; Infection; Monoclonal Antibodies; Mus; Oryctolagus cuniculus; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phenotype; Plasma; Polysaccharides; Population; Race; Reagent; Recombinants; Recording of previous events; Reporting; Resistance; Risk; Risk Behaviors; Sampling; Sequence Analysis; Specificity; Specimen; Subunit Vaccines; Testing; Time; Universities; Vaccine Design; Vaccine Research; Vaccines; Viral Load result; Viral Proteins; Viral load measurement; Virus; Virus Replication; Woman; Women’s Interagency HIV Study; antiretroviral therapy; base; clinical development; cohort; design; env Gene Products; env Genes; genetic analysis; human monoclonal antibodies; immunogenicity; injection drug use; neutralizing antibody; neutralizing monoclonal antibodies; novel; prevent; public health relevance; reconstruction; screening; seropositive; transmission process; vaccine candidate; vaccine development; vaccine efficacy; vaccine trial; viral RNA; virtual

DESCRIPTION (provided by applicant): The overall objective of this proposal is to collect data leading to the development of a vaccine able to prevent HIV-1 infection in African American women who are at risk for infection as a direct or indirect consequence of drug abuse. Although they represent only 14% of the female population in the US, African American women make up 66% of all new HIV/AIDS cases among women in reporting states. While direct injection drug use is the second major cause of HIV-1 infections in women, multiple studies have shown that other forms of drug abuse by women, or their partners, are a proximal cause of heterosexual transmission of HIV. Despite their disproportionate risk of infection, few if any vaccine development efforts have focused on African American women. In this proposal, we will first collect data on viruses and antibody responses in this group that could facilitate the development of vaccines designed to elicit broadly neutralizing antibodies (bNAbs). Information of this type includes defining novel epitopes recognized by bNAbs found in these subjects. We will then seek to recover HIV envelope genes from a rare group of subjects who possess high levels of bNAbs and are able to control their viral loads without antiretroviral therapy (ART). While patients able to control viral loads between 50 and 2000 copies/ml and possess bNAbs (viremic controllers) have been known for some time, only recently have individuals able to maintain viral loads at undetectable levels and possess bNAbs been identified. These individuals possess the dual "elite neutralizer" (EN), "elite controller" (EC) phenotype. Preliminary data suggest that this phenotype may be more common in HCV-infected African American women than other risk groups. We will then use genetic analysis, including ancestral reconstruction, to recover and characterize the envelope genes that gave rise to bNAb responses in these subjects. We will use these genes to produce recombinant envelope proteins (rgp120 and gp140) and test these as candidate vaccine immunogens in small animal immunogenicity studies. After more than 25 years of vaccine research, none of the HIV vaccines described to date are able to consistently elicit broadly neutralizing antibodies. Moreover, all of the vaccine immunogens in clinical development to date were selected without regard to the neutralizing antibody response in the virus donor. The studies in this proposal will be the first studies to evaluate the efficacy of vaccine immunogens known to have stimulated bNAbs in humans. These will also be the first studies to attempt to replicate the protective immune response seen in a rare group of African American women who have developed effective antiviral immune responses to HIV.

描述（由申请人提供）：本提案的总体目标是收集数据，以开发一种能够预防因药物滥用而直接或间接面临感染风险的非裔美国妇女感染HIV-1的疫苗。虽然她们只占美国女性人口的14%，但非洲裔美国妇女占报告州妇女中所有新艾滋病毒/艾滋病病例的66%。虽然直接注射吸毒是妇女感染艾滋病毒-1的第二大原因，但多项研究表明，妇女或其伴侣滥用其他形式的药物是艾滋病毒异性传播的一个近因。尽管她们感染的风险不成比例，但很少有疫苗开发工作集中在非洲裔美国妇女身上。在本提案中，我们将首先收集该组中有关病毒和抗体应答的数据，这些数据可以促进旨在引发广泛中和抗体（bNAb）的疫苗的开发。这种类型的信息包括定义在这些受试者中发现的bNAb识别的新表位。然后，我们将寻求从一组罕见的受试者中恢复HIV包膜基因，这些受试者具有高水平的bNAb，并且能够在没有抗逆转录病毒治疗（ART）的情况下控制其病毒载量。虽然已知患者能够将病毒载量控制在50至2000拷贝/ml之间并拥有bNAb（病毒血症控制者）已有一段时间，但直到最近才鉴定出能够将病毒载量维持在不可检测水平并拥有bNAb的个体。这些个体具有双重“精英中和者”（EN）、“精英控制者”（EC）表型。初步数据表明，这种表型可能更常见于HCV感染的非洲裔美国妇女比其他风险群体。然后，我们将使用遗传分析，包括祖先重建，恢复和表征的信封基因，引起了bNAb的反应，在这些科目。我们将使用这些基因来生产重组包膜蛋白（rgp 120和gp 140），并在小动物免疫原性研究中将其作为候选疫苗免疫原进行测试。经过超过25年的疫苗研究，迄今为止所描述的艾滋病毒疫苗中没有一种能够持续地引起广泛中和抗体。此外，迄今为止，临床开发中的所有疫苗免疫原都是在不考虑病毒供体中的中和抗体应答的情况下选择的。本提案中的研究将是第一个评估已知刺激人体bNAb的疫苗免疫原有效性的研究。这些也将是第一个试图复制保护性免疫反应的研究，这些保护性免疫反应在一组罕见的非洲裔美国妇女中观察到，这些妇女已经对艾滋病毒产生了有效的抗病毒免疫反应。

项目成果

Ancestral sequences from an elite neutralizer proximal to the development of neutralization resistance as a potential source of HIV vaccine immunogens.

来自精英中和剂的祖先序列，接近中和抗性的发展，作为 HIV 疫苗免疫原的潜在来源。

• DOI: 10.1371/journal.pone.0213409
• 发表时间: 2019
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Mesa,KathrynA;Yu,Bin;Wrin,Terri;Petropoulos,ChristosJ;Pogson,GrantH;Alexander,DavidL;Perez,Gerardo;O'Rourke,SaraM;Sinangil,Faruk;Robinson,Joseph;Conant,MarcusA;Berman,PhillipW
• 通讯作者: Berman,PhillipW

Identification and CRISPR/Cas9 Inactivation of the C1s Protease Responsible for Proteolysis of Recombinant Proteins Produced in CHO Cells.

负责 CHO 细胞中产生的重组蛋白水解的 C1s 蛋白酶的鉴定和 CRISPR/Cas9 灭活。

• DOI: 10.1002/bit.27016
• 发表时间: 2019
• 期刊: Biotechnology and bioengineering
• 影响因子: 3.8
• 作者: Li,SophiaW;Yu,Bin;Byrne,Gabriel;Wright,Meredith;O'Rourke,Sara;Mesa,Kathryn;Berman,PhillipW
• 通讯作者: Berman,PhillipW