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项重大的全球危机。目前，95%以上的艾滋病毒感染者生活在发展中国家，95%与艾滋病毒-1相关的死亡发生在发展中国家。大多数死者正值壮年，夺走了社会中最具生产力的工人，给社会的基础设施造成了沉重的负担，并造成了大量艾滋病孤儿。在这些国家，慢性寄生虫感染增加了艾滋病疫苗研制的复杂性。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，约有15亿人携带寄生虫负担。这些人存在于一种恒定的免疫激活状态，其特征是主导Th2型细胞因子谱，高IgE水平和嗜酸性粒细胞增多。这种免疫特征可能对疫苗，特别是艾滋病毒-1疫苗的效力产生不利影响。必须处理寄生虫感染对疫苗效力的影响，以确保假定的疫苗有尽可能高的实地成功机会。目前，只有少数关于慢性寄生虫感染对假定的HIV-1疫苗的影响的研究。我提出的项目的目标是研究慢性寄生虫感染和由此产生的Th2免疫谱对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小鼠的利什曼原虫主要感染（还有其他几种优秀的系统，包括血吸虫，可能在后续研究中使用）。L. major感染Balb/c小鼠导致Th2免疫谱模拟可能在HIV-1感染个体的临床观察。在确定慢性寄生虫感染后，将用DNA HIV-1疫苗对小鼠进行免疫（据报道，这种疫苗可以控制病毒复制并保护灵长类动物免受CD4细胞损失）。将评估CD8和CD4对HIV-1抗原反应的水平和质量。此外，我们将扩大我们的研究，通过共同给药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。这一建议代表了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.