Parasitic Infection Alters Quality of Immune Response

寄生虫感染改变免疫反应的质量

• 批准号: 6553833
• 负责人: Jean D Boyer
• 金额: $ 23.78万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-15 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6553833
• 关键词: AIDS vaccines; HIV infections; Leishmania major; active immunization; comorbidity; cytotoxic T lymphocyte; drug screening /evaluation; helper T lymphocyte; human immunodeficiency virus 1; immunomodulators; interleukin 12; interleukin 15; interleukin 2; laboratory mouse; leishmaniasis; leukocyte activation /transformation; parasite infection mechanism; vector vaccine

DESCRIPTION (provided by applicant): The AIDS epidemic in the Developing World represents a major global crisis. More than 95% of all HIV-infected people now live in the Developing World, and 95% percent of all HIV-1 related deaths have occurred among its people. Most who have died were in the prime of life, robbing their societies of their most productive workers severely taxing their infrastructures, and creating a large population of AIDS orphans. In these countries, chronic parasitic infection adds another level of complexity to AIDS vaccine development. Helminthic and protozoan infections are common in developing countries. The most conservative numbers suggest that approximately 1.5 billion people carry a parasitic burden. These persons exist in a constant state of immune activation that is characterized by a dominant Th2 type of cytokine profile, high IgE levels, and eosinophilia. Such an immune profile may have an adverse impact on the efficacy of vaccines in particular an HIV-1 vaccine. The impact of parasitic infection on vaccine effectiveness must be addressed to ensure that putative vaccines have the highest possible chance for field success. Currently there have been only a few studies of the effects of chronic parasitic infection on putative HIV-1 vaccines. The goal of my proposed project will be to study the impact of chronic parasitic infection and the resulting Th2 immune profile on an HIV-1 vaccine induced immune response. The model we will use is Leishmania major infection in Balb/c mice (there are several other excellent systems, including Schistosoma manosi, that may be used in subsequent studies). L. major infection in Balb/c mice leads to a Th2 immune profile mimicking what might be seen in the clinic in HIV-1 infected individuals. Following the establishment of chronic parasitic infection the mice will be immunized with a DNA HIV-1 vaccine (that has been reported to control viral replication and protect primates from CD4 loss). The level and quality of CD8 and CD4 responses against HIV-1 antigens will be assessed. Further, we will expand our studies to look at the effects of putative Th1 type cytokines in this model through co-administration of the HIV-1 vaccine and cytokine expressing plasmids. This proposal represents the initiation of a new and important area of research.

描述（由申请人提供）：发展中国家的艾滋病流行代表着一场重大的全球危机。 目前，超过 95% 的 HIV 感染者生活在发展中国家，95% 的 HIV-1 相关死亡都发生在发展中国家。 大多数死者都正值壮年，他们的社会失去了生产力最高的工人，给基础设施带来了沉重的负担，并造成了大量艾滋病孤儿。 在这些国家，慢性寄生虫感染使艾滋病疫苗的开发变得更加复杂。蠕虫和原虫感染在发展中国家很常见。 最保守的数字表明，大约有 15 亿人患有寄生负担。这些人处于持续的免疫激活状态，其特征是 Th2 型细胞因子谱占主导地位、高 IgE 水平和嗜酸性粒细胞增多。 这种免疫特征可能对疫苗尤其是HIV-1疫苗的功效产生不利影响。 必须解决寄生虫感染对疫苗有效性的影响，以确保推定的疫苗具有最大可能的现场成功机会。 目前，关于慢性寄生虫感染对假定的 HIV-1 疫苗的影响的研究很少。 我提议的项目的目标是研究慢性寄生虫感染以及由此产生的 Th2 免疫特征对 HIV-1 疫苗诱导的免疫反应的影响。 我们将使用的模型是Balb/c小鼠的利什曼原虫重度感染（还有其他几个优秀的系统，包括Schistosoma manosi，可能会在后续研究中使用）。 Balb/c 小鼠中的 L. Major 感染导致 Th2 免疫特征与临床上 HIV-1 感染者的免疫特征相似。 建立慢性寄生虫感染后，将对小鼠进行 DNA HIV-1 疫苗免疫（据报道，该疫苗可以控制病毒复制并保护灵长类动物免受 CD4 损失）。 将评估针对 HIV-1 抗原的 CD8 和 CD4 反应的水平和质量。 此外，我们将扩大研究范围，通过同时施用 HIV-1 疫苗和细胞因子表达质粒来观察假定的 Th1 型细胞因子在该模型中的作用。 该提案代表了一个新的重要研究领域的开始。