An endogenous retroelement vaccine against HIV-1

一种针对 HIV-1 的内源性逆转录病毒疫苗

• 批准号: 7904379
• 负责人: DOUGLAS F NIXON
• 金额: $ 42.49万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-12 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7904379
• 关键词: AIDS/HIV problem; Acute; Anti-Retroviral Agents; Antigens; Applications Grants; Autologous; Biological Assay; CD4 Positive T Lymphocytes; Cells; Cytomegalovirus; DNA Insertion Elements; Data; Elements; Epitopes; Event; Fossils; Genome; Genomics; Goals; Grant; HERVs; HIV; HIV Infections; HIV-1; Human; Human Genome; Immune response; In Vitro; Individual; Infection; Infectious Agent; Junk DNA; Kinetics; Lead; Maps; Nuclear; Paste substance; Pathogenesis; Peptides; Pharmaceutical Preparations; Plasma; Prevalence; Primates; Proliferating; Response Elements; Retroelements; Retrotransposition; Short Interspersed Nucleotide Elements; Specificity; Surrogate Markers; T-Lymphocyte; Testing; Time; Transcript; Vaccination; Vaccine Design; Vaccines; Variant; Viral; Viral Load result; Virus; Work; base; cross reactivity; design; in vitro testing; innovation; killings; macrophage; novel strategies; novel vaccines; resistance factors; response; synthetic peptide; transmission process

Project Summary Human endogenous retrotransposable elements (HEREs) make up approximately 42% of the human genome. Included amongst these elements are the LTR associated human endogenous retrovirus insertions (HERVs), and the non-LTR associated long and short interspersed nuclear elements (LINE and SINE). The prevalence of HERV elements has resulted from the accumulation of past retroviral infectious agents that have entered the germline and established a truce with the host cell. LINE and SINE elements, which are not thought to have been derived from infectious precursors, have proliferated throughout the genome by a 'copy and paste' retrotransposition mechanism. Recent data have shown that these elements are under the cellular control of the innate resistance factors APOBEC3B, 3A, 3F and 3G. We have generated data that shows HIV-1 infection of primary CD4+ T cells and macrophages in vitro resulted in enhanced levels of HERE transcripts, and the accumulation of additional HERE genomic copies, indicating the induction of successfully completed retrotransposition events. HERE transcripts in the plasma were detected in individuals with acute/early HIV-1 infection not on antiretroviral drug treatment. These latter individuals had detectable ex vivo T cell responses to HERV antigens, and the magnitude of the anti-HERE response inversely correlated with HIV-1 plasma viral load. This grant proposes in one specific aim to determine whether the immune response generated to these elements can eliminate HIV-1 infected cells. We will determine the relationship between anti-HERE T cell response and HIV-1 plasma viral load, and how anti-HERE T cell clones recognize virus infected cells in vitro and if they can suppress HIV-1 viral replication in a viral inhibition assay. Elicitation of T cells against HEREs by vaccination would lead to T cell recognition of HIV-1 via both cross-reactivity between HEREs and HIV-1 and independent recognition of HERE antigens produced by HIV-1 infected cells. The work proposed in this grant aims to generate data for a novel vaccine strategy against HIV-1.

项目摘要 人类内源性逆转座子(HERES)约占人类基因组的42%。 这些元件中包括LTR相关的人内源性逆转录病毒插入(HERV)， 非LTR伴生的长短穿插核素(线状和正弦)。流行率 HERV成分的产生是由于过去进入美国的逆转录病毒感染剂的积累 并与宿主细胞休战。直线和正弦元素，它们被认为不具有 来源于感染性前体，通过复制粘贴在整个基因组中增殖 逆转位机制。最近的数据表明，这些元素处于细胞控制之下 先天抗性因子APOBEC3B、3A、3F和3G。我们已经生成了显示HIV-1感染的数据 体外培养的原代CD4+T细胞和巨噬细胞导致HERE转录本水平升高，并且 额外的HERE基因组拷贝的积累，表明诱导成功完成 逆转位事件。这里检测到的是急性/早期HIV-1感染者血浆中的转录本。 感染不接受抗逆转录病毒药物治疗。后者具有可检测到的体外T细胞反应 HERV抗原和抗HERE反应的大小与HIV-1血浆病毒呈负相关 装填。这项资助提出了一个特定的目标，以确定对这些细胞产生的免疫反应 元素可以消除HIV-1感染细胞。我们将确定抗HERE T细胞之间的关系 应答和HIV-1血浆病毒载量，以及抗HERE T细胞克隆如何在体外识别病毒感染的细胞 以及他们是否能在病毒抑制试验中抑制HIV-1病毒的复制。T细胞对HERES的诱导作用 通过接种疫苗将通过HERE和HIV-1之间的交叉反应导致T细胞识别HIV-1 以及对HIV-1感染细胞产生的HERE抗原的独立识别。在本报告中提出的工作 格兰特的目标是为针对HIV-1的一种新的疫苗战略产生数据。