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

基本信息

批准号：
8895901
负责人：
Phillip Wayne Berman
金额：
$ 58.82万
依托单位：
UNIVERSITY OF CALIFORNIA SANTA CRUZ
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8895901
关键词：
AIDS/HIV problem Accounting African American American Animals Anti-Retroviral Agents Antibodies Antibody Response Antigens Antiviral Agents Biological Assay Clinical Cohort Studies Collaborations DNA Data Development Disease Progression Drug abuse Epitopes Ethnic Origin Exhibits Female Genes Genetic Goals HIV HIV Envelope Protein gp120 HIV Infections HIV vaccine HIV-1 Health Hepatitis C virus Heterosexuals Human Immune response Immunization Immunologics Individual Infection Monoclonal Antibodies Mus Oryctolagus cuniculus Patients Pharmaceutical Preparations Pharmacotherapy Phase Phenotype Plasma Population Race Reagent Recombinants Recording of previous events Reporting Resistance Risk Risk Behaviors Sampling Sequence Analysis Serum Specificity Specimen Subunit Vaccines Testing Time Universities Vaccine Design Vaccine Research Vaccines Viral Viral Load result Viral Proteins Viral load measurement Virus Virus Replication Woman antiretroviral therapy base cohort design env Gene Products env Genes genetic analysis human monoclonal antibodies immunogenicity injection drug use neutralizing antibody novel prevent reconstruction response screening seropositive transmission process vaccine candidate vaccine development vaccine efficacy vaccine trial viral RNA

项目摘要

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导致感染风险的非裔美国妇女感染 HIV-1 的疫苗。尽管非裔美国女性仅占美国女性人口的 14%，但在报告州的所有新发艾滋病毒/艾滋病病例中，非裔美国女性却占到了 66%。虽然直接注射吸毒是女性感染 HIV-1 的第二大原因，但多项研究表明，女性或其伴侣其他形式的吸毒行为是异性传播 HIV 的最直接原因。尽管感染风险不成比例，但很少有疫苗开发工作集中在非裔美国女性身上。在这项提案中，我们将首先收集该组病毒和抗体反应的数据，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。此类信息包括定义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，这些受试者拥有高水平的 bNAb，并且能够在不接受抗逆转录病毒治疗 (ART) 的情况下控制其病毒载量。虽然人们已经知道能够将病毒载量控制在 50 至 2000 拷贝/毫升之间并拥有 bNAb（病毒血症控制剂）的患者有一段时间了，但直到最近才发现个体能够将病毒载量维持在不可检测的水平并拥有 bNAb。这些个体具有双重“精英中和者”（EN）和“精英控制者”（EC）表型。初步数据表明，这种表型在感染 HCV 的非裔美国女性中可能比其他危险人群更常见。然后，我们将使用遗传分析（包括祖先重建）来恢复和表征在这些受试者中引起 bNAb 反应的包膜基因。我们将使用这些基因生产重组包膜蛋白（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进行测试。经过超过 25 年的疫苗研究，迄今为止所描述的 HIV 疫苗均无法持续引发广泛中和抗体。此外，迄今为止临床开发中的所有疫苗免疫原的选择都没有考虑病毒供体中的中和抗体反应。该提案中的研究将是第一个评估已知可刺激人类 bNAb 的疫苗免疫原功效的研究。这些也将是首次尝试复制在少数非裔美国女性中观察到的保护性免疫反应的研究，这些女性已经对艾滋病毒产生了有效的抗病毒免疫反应。