Parasitic Infection Alters Quality of Immune Response

描述（由申请人提供）：艾滋病在发展中国家的流行是一个重大的全球危机。 目前，95%以上的艾滋病毒感染者生活在发展中国家，95%的艾滋病毒-1相关死亡发生在发展中国家。 大多数死者正值壮年，使社会失去了最有生产力的工人，给基础设施带来沉重负担，并造成大量艾滋病孤儿。 在这些国家，慢性寄生虫感染给艾滋病疫苗开发增加了另一个复杂程度。蠕虫和原生动物感染在发展中国家很常见。 最保守的数字表明，大约有15亿人背负着寄生虫的负担。这些人存在于一个恒定的免疫激活状态，其特征在于占主导地位的Th 2型细胞因子谱，高IgE水平，嗜酸性粒细胞增多症。 这样的免疫特性可能对疫苗特别是HIV-1疫苗的效力具有不利影响。 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田间成功机会。 目前，只有少数研究慢性寄生虫感染对推定的HIV-1疫苗的影响。 我提出的项目的目标将是研究慢性寄生虫感染和由此产生的Th 2免疫对HIV-1疫苗诱导的免疫应答的影响。 我们将使用的模型是Balb/c小鼠中的主要利什曼原虫感染（还有其他几个优秀的系统，包括马诺西血吸虫，可用于后续研究）。L. Balb/c小鼠中的主要感染导致Th 2免疫特征，其模拟在HIV-1感染个体中的临床中可能看到的特征。 在建立慢性寄生虫感染后，小鼠将用DNA HIV-1疫苗免疫（据报道，该疫苗可控制病毒复制并保护灵长类动物免受CD 4损失）。 将评估针对HIV-1抗原的CD 8和CD 4应答的水平和质量。 此外，我们将扩大我们的研究，通过共同管理的HIV-1疫苗和细胞因子表达质粒，在这个模型中，看看推定的Th 1型细胞因子的影响。 这一建议代表着一个新的重要研究领域的开始。

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.