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HIV-1 immunity: Innate immune correlates and vaccine responses.

机译：HIV-1免疫：先天免疫相关性和疫苗反应。

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摘要

HIV-1 infection represents one of the greatest threats to global health in the modern era. Efforts to develop a vaccine against HIV-1 have been hampered by a lack of knowledge regarding what type of immune response best affords protection from HIV-1 infection and subsequent disease progression. To elucidate immune mechanisms that may serve to protect individuals against HIV-1 infection and disease by mounting altered innate pro-inflammatory or antiviral responses, I investigated Toll-like receptor (TLR) function and genetic polymorphisms in cohorts of individuals with varying susceptibility to HIV-1 infection (exposed seronegative [ES] individuals) and variable courses of disease progression. I discovered that myeloid dendritic cells from ES individuals exhibited reduced responsiveness to LPS when compared to low-risk HIV-uninfected controls, and, separately, that a common non-synonymous TLR4 single-nucleotide polymorphism, D299G, was associated with higher viral loads in HIV-infected subjects. In addition, to determine how T-cell responses to an adenovirus-vector HIV-1 vaccine candidate are affected by pre-existing adenovirus-specific immunity, I developed a novel cytokine profiling assay to measure T-cell responses to both the gag transgene and Adenovirus serotype 5 (Ad5) vector in an MRKAd5 HIV-1 Gag phase I trial. I determined that pre-existing Ad5 immunity is a potent determinant of the HIV-specific vaccine-induced response, and that the presence of Ad5 neutralizing antibodies is not a useful predictor of cellular responses to the Ad5 vector. Altogether, my results demonstrate that variability among individual innate immune responses and pre-existing natural infections may contribute to the varying outcomes of exposure to HIV antigens, both in the context of natural infection and vaccination.
机译：HIV-1感染是现代社会对全球健康的最大威胁之一。由于缺乏关于哪种免疫应答最能提供免受HIV-1感染和随后疾病发展的保护的知识，阻碍了开发抗HIV-1疫苗的努力。为了阐明可以通过改变先天的促炎性或抗病毒反应来保护个体免受HIV-1感染和疾病侵袭的免疫机制，我研究了Toll样受体（TLR）功能和遗传多态性在不同人群对HIV易感性的人群中-1感染（暴露于血清阴性的[ES]个体）和疾病进程的变化过程。我发现与低风险的HIV未感染对照相比，ES个体的髓样树突状细胞对LPS的反应降低，并且，另外一个常见的非同义TLR4单核苷酸多态性D299G与更高的病毒载量相关感染了HIV的受试者。此外，为了确定对腺病毒载体HIV-1疫苗候选者的T细胞反应如何受到预先存在的腺病毒特异性免疫的影响，我开发了一种新型的细胞因子谱分析法来测量对gag转基因和在MRKAd5 HIV-1 Gag I期试验中，腺病毒血清型5（Ad5）载体。我确定预先存在的Ad5免疫力是HIV特异性疫苗诱导的应答的有效决定因素，并且Ad5中和抗体的存在不是对Ad5载体细胞应答的有用预测指标。总之，我的结果表明，在自然感染和疫苗接种的情况下，个体先天免疫反应和先前存在的自然感染之间的差异可能会导致暴露于HIV抗原的结果有所不同。

著录项

  • 作者

    Pine, Samuel O'Neill.;

  • 作者单位

    University of Washington.;

  • 授予单位 University of Washington.;
  • 学科 Biology Virology.;Health Sciences Immunology.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 126 p.
  • 总页数 126
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

  • 入库时间 2022-08-17 11:38:19

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