Effect of Helminth Infection on HIV-1 Vaccines

蠕虫感染对 HIV-1 疫苗的影响

• 批准号: 7494355
• 负责人: Donald A Harn
• 金额: $ 40.75万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-15 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7494355
• 关键词: AIDS vaccine development; AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Adenovirus Vector; Africa South of the Sahara; Antibodies; Antibody Formation; Automobile Driving; Bacterial Typing; Bacterial Vaccines; Brazil; CD8B1 gene; Calmette-Guerin Bacillus; Cells; China; Clinical Trials; Country; Cytotoxic T-Lymphocytes; DNA Vaccines; Developed Countries; Developing Countries; Development; Disease; Epidemic; Face; Goals; HIV vaccine; HIV-1; HIV-1 vaccine; Helminths; High Prevalence; Human; Immune; Immune response; Immune system; India; Individual; Infection; Joints; Life; Modeling; Mucosal Immunity; Mus; Parasites; Persons; Pharmaceutical Preparations; Play; Population; Populations at Risk; Praziquantel; Prevalence; Public Health; Research Personnel; Role; Route; Schistosoma; Schistosoma mansoni; Schistosoma mansonii infection; Southern Africa; T memory cell; T-Lymphocyte; Testing; Tetanus Toxin; Time; Treatment Protocols; United Nations; Vaccinated; Vaccination; Vaccine Design; Vaccines; Viral; Viral Antigens; Virus; cytotoxic; design; gag Gene Products; immune function; immunoregulation; macrophage; mucosal site; mucosal vaccine; neutralizing antibody; pandemic disease; pathogen; plasmid DNA; programs; research study; response; restoration; success; transmission process; vector vaccine

DESCRIPTION (provided by applicant): The worldwide AIDS epidemic is most devastating in developing countries where more than 40 million people are infected. The development of an HIV-1 vaccine for populations in southern Africa and other developing countries is the highest priority. The majority of inhabitants in developing countries are also infected with parasitic helminthes which drive Th2-biasing and immune suppression. Helminth infection suppresses immune responses to Th1-type vaccines, and the expansion of viral antigen specific CD4+ and CD8+ T cell responses. Th1-type and cytotoxic CD8+ T cell responses are the goal of the majority of HIV-1 candidate vaccines in development or in clinical trials. Thus, how helminth infection will impact not only the induction of robust T cell responses to candidate HIV-1 vaccines but also the durability of these T cell responses is an important question. DNA/Adenoviral vector vaccines have shown great success in driving systemic and or mucosal vaccine-specific antibody, CD4+ and CD8+ T cell responses to HIV-1, as well as other pathogens. Thus the first goal of this application is to determine if DNA/Adenoviral vector HIV-1 vaccines will induce strong vaccine specific T cell responses following elimination of helminth parasites. To mimic the scenario in developing countries, we next ask if these vaccine specific T cell responses are maintained in mice that become re-infected with helminth parasites. In this same regard we will determine how re-infection during the vaccination regimen impacts the induction of vaccine specific T cell responses. We will also determine whether F4/80+,Gr1+ suppressor macrophages and/or CD4+,CD25+ T regulatory cells play prominent roles in suppression of HIV-1 vaccine specific T cell responses in helminth mice. Lastly, because the majority of HIV-1 transmission in developing countries is via mucosal sites, we ask if helminth infection differentially impacts systemic vs mucosal HIV-1 vaccine specific T cell responses in helminth infected mice. The specific aims of this proposal are: 1) Will eradication of schistosome infection and restoration of normal immune bias allow for successful vaccination with HIV-1 candidate vaccines in mice? 2) Will established immune responses to HIV-1 vaccines remain durable or be altered by subsequent infection with immunomodulatory helminthes? 3) Does helminth infection differentially impact systemic vs mucosal HIV-1 vaccine specific T cell responses? PUBLIC HEALTH RELEVANCE: The HIV-1 pandemic remains one of the greatest global disease threats we face. The majority of infected individuals as well as the "at-risk" populations reside in sub-saharan Africa and other developing countries. Tremendous effort has been put forth to develop HIV-vaccines for these populations and many are currently in trial. Most of the individuals in sub-saharan Africa and other developing countries are also infected with immune suppressive helminth parasites which have been shown to negatively impact vaccination with BCG and tetanus toxin. No one has examined the impact of earlier helminth infection on HIV-1 vaccination, nor what happens to HIV-1 vaccine induced immune responses following reinfection with immune suppressive helminthes. This study is designed to answer both of these questions.

描述（由申请人提供）：全球艾滋病流行在发展中国家最具破坏性，超过4000万人感染。为南部非洲和其他发展中国家的人口研制艾滋病毒-1疫苗是最高优先事项。发展中国家的大多数居民也感染了寄生蠕虫，这些蠕虫驱动Th 2偏置和免疫抑制。蠕虫感染抑制对Th 1型疫苗的免疫应答，以及病毒抗原特异性CD 4+和CD 8 + T细胞应答的扩增。Th 1型和细胞毒性CD 8 + T细胞应答是大多数HIV-1候选疫苗在开发或临床试验中的目标。因此，蠕虫感染如何不仅影响对候选HIV-1疫苗的稳健T细胞应答的诱导，而且影响这些T细胞应答的持久性是一个重要的问题。DNA/腺病毒载体疫苗在驱动针对HIV-1以及其他病原体的全身和/或粘膜疫苗特异性抗体、CD 4+和CD 8 + T细胞应答方面已经显示出巨大的成功。因此，本申请的第一个目标是确定DNA/腺病毒载体HIV-1疫苗在消除蠕虫寄生虫后是否会诱导强烈的疫苗特异性T细胞应答。为了模拟发展中国家的情况，我们接下来询问这些疫苗特异性T细胞应答是否在再次感染蠕虫寄生虫的小鼠中维持。在这方面，我们将确定疫苗接种方案期间的再感染如何影响疫苗特异性T细胞应答的诱导。我们还将确定F4/80+、Gr 1+抑制性巨噬细胞和/或CD 4+、CD 25 + T调节细胞是否在蠕虫小鼠中抑制HIV-1疫苗特异性T细胞应答中发挥重要作用。最后，因为大多数HIV-1在发展中国家的传播是通过粘膜网站，我们问蠕虫感染是否差异影响系统与粘膜HIV-1疫苗特异性T细胞反应蠕虫感染的小鼠。该提案的具体目标是：1）根除HIV-1感染和恢复正常免疫偏倚是否允许在小鼠中成功接种HIV-1候选疫苗？2)对HIV-1疫苗的既定免疫反应是否会保持持久，或者会因随后感染免疫调节蠕虫而改变？3)寄生虫感染对系统性与粘膜HIV-1疫苗特异性T细胞应答的影响是否不同？公共卫生相关性：HIV-1大流行病仍然是我们面临的最大全球疾病威胁之一。大多数受感染者以及“高危”人群居住在撒哈拉以南非洲和其他发展中国家。为这些人群研制艾滋病毒疫苗已经付出了巨大的努力，许多疫苗目前正在试验中。撒哈拉以南非洲和其他发展中国家的大多数人也感染了免疫抑制性蠕虫寄生虫，这些寄生虫已被证明会对卡介苗和破伤风毒素的接种产生负面影响。没有人研究过早期蠕虫感染对HIV-1疫苗接种的影响，也没有人研究过免疫抑制蠕虫再次感染后HIV-1疫苗诱导的免疫应答会发生什么。本研究旨在回答这两个问题。