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; 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）：该提案的总体目的是收集数据，以开发能够防止有毒品滥用的直接或间接后果的非裔美国人妇女中的HIV-1感染。尽管他们仅占美国女性人口的14％，但在报告州，妇女中，非裔美国妇女占所有新艾滋病毒/艾滋病案件的66％。虽然直接注射药物的使用是女性HIV-1感染的第二个主要原因，但多项研究表明，其他形式的妇女或其伴侣滥用药物滥用是艾滋病毒异性传播的近端原因。尽管他们出现感染的风险不成比例，但很少有任何疫苗开发工作集中在非裔美国妇女上。在此提案中，我们将首先收集该组中有关病毒和抗体反应的数据，这些数据可能促进旨在引起广泛中和抗体（BNABS）的疫苗的开发。这种类型的信息包括定义由这些受试者发现的BNAB识别的新型表位。然后，我们将寻求从拥有高水平的BNAB的罕见受试者中回收HIV包膜基因，并且能够控制其病毒载量而无需抗逆转录病毒疗法（ART）。虽然能够控制50至2000份/mL的病毒载荷和拥有BNAB（病毒控制器）的患者已知一段时间，但直到最近才有能够在无法检测到的水平上保持病毒载量并鉴定出BNAB。这些人具有双重“精英中和器”（EN），“精英控制器”（EC）表型。初步数据表明，与其他风险群体相比，在HCV感染的非裔美国妇女中，这种表型可能更常见。然后，我们将使用包括祖先重建在内的遗传分析来恢复和表征产生这些受试者BNAB反应的包膜基因。我们将使用这些基因产生重组包膜蛋白（RGP120和GP140），并在小动物免疫原性研究中将其作为候选疫苗免疫原子进行测试。经过25年以上的疫苗研究，迄今为止所描述的HIV疫苗都无法始终如一地引起广泛中和抗体。此外，迄今为止选择了临床发育中的所有疫苗免疫原，而无需考虑病毒供体中中和抗体反应。该提案中的研究将是最早评估已知已刺激人类BNAB的疫苗免疫原子疗效的研究。这些也将是第一个尝试复制在罕见的非洲裔美国妇女中看到的保护性免疫反应的研究，这些非洲裔美国妇女对艾滋病毒产生了有效的抗病毒免疫反应。