Dissecting the effects of filarial-associated immunomodulation on HIV susceptibility

剖析丝虫相关免疫调节对 HIV 易感性的影响

• 批准号: 317234751
• 负责人: Professor Dr. Achim Hoerauf
• 金额: --
• 依托单位: Abteilung für Infektions- und Tropenmedizin
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/317234751?language=en
• 关键词: Dissecting; effects; filarial; associated; immunomodulation

The rapid spread of HIV over the last decades in Sub-Saharan Africa has led to different hypotheses to explain this phenomenon. One well-known hypothesis implies that specific pre-existing helminth infections contribute to systemic immune activation, which facilitates early viral dissemination hence increases susceptibility to HIV. In a recent prospective study in Tanzania, our consortium have demonstrated, for the first time, that there is a significant increased risk of acquiring HIV in individuals presenting lymphatic filariasis (LF), especially in 14-30 year olds. LF is known to induce immune-regulation in the host and preliminary findings from this consortium have shown that LF-infected individuals have increased frequencies of activated CD4+ T cells whereas CD8+ T cells showed markers of exhaustion. Interestingly, exhausted CD8+ T cells were only found in patent individuals, those with peripheral microfilaria (MF), the worms offspring. This study will continue to investigate immune-epidemiological associations of LF and HIV in endemic areas of Ghana and Tanzania. First, a follow up study with same Tanzanian cohort will determine the effects of long-term mass drug administration (MDA) on HIV incidence. Since MDA was applied only after the initial study began we are in a unique position to address this question and moreover, decipher immunological changes in this cohort in a longitudinal manner. Further field studies in Ghana will assess the prevalence of HIV in endemic areas of LF and onchocerciasis providing information about whether the increased susceptibility is restricted to LF infections or a phenomenon of filariae per se. Furthermore, by sub-dividing the LF-infected individuals into infection state (MF+ vs. MF-), we will determine whether the observed association is MF-dependent and moreover, through immune profiling gain new insights into filarial-induced mechanisms that drive enhanced susceptibility. Finally, in vitro PBMC stimulation using transgenic HSA-HIV strains and antigens derived from different filarial species, immune responses in different infection scenarios will be analyzed. In summary, this study aims to elucidate the mechanisms underlying the increased susceptibility for HIV in LF-infected individuals and will provide novel insights into parasite-host-virus interactions.

过去几十年来，艾滋病毒在撒哈拉以南非洲地区的迅速传播导致了不同的假设来解释这一现象。一个众所周知的假设意味着特定的预先存在的蠕虫感染有助于全身免疫激活，这有助于早期病毒传播，从而增加对HIV的易感性。在坦桑尼亚最近的一项前瞻性研究中，我们的联合体首次证明，淋巴丝虫病（LF）患者感染艾滋病毒的风险显著增加，特别是在14-30奥尔兹中。已知LF在宿主中诱导免疫调节，并且来自该联合体的初步发现表明，LF感染的个体具有增加的活化的CD 4 + T细胞的频率，而CD 8 + T细胞显示衰竭的标志物。有趣的是，耗尽的CD 8 + T细胞仅在患者中发现，即那些患有外周微丝蚴（MF）的人，即蠕虫的后代。这项研究将继续调查免疫流行病学协会LF和艾滋病毒在加纳和坦桑尼亚的流行地区。首先，对同一坦桑尼亚队列的随访研究将确定长期大规模药物管理（MDA）对艾滋病毒发病率的影响。由于MDA仅在初始研究开始后应用，因此我们处于独特的位置来解决这个问题，并且以纵向方式解释该队列中的免疫学变化。在加纳进行的进一步实地研究将评估LF和盘尾丝虫病流行地区的艾滋病毒流行情况，提供关于易感性增加是否仅限于LF感染或丝虫病现象本身的信息。此外，通过将LF感染个体细分为感染状态（MF+ vs. MF-），我们将确定观察到的关联是否是MF依赖性的，此外，通过免疫分析获得对驱动易感性增强的丝虫诱导机制的新见解。最后，使用转基因HSA-HIV毒株和来自不同丝虫物种的抗原体外刺激PBMC，分析不同感染情况下的免疫应答。总之，本研究旨在阐明LF感染个体对HIV易感性增加的机制，并将为寄生虫-宿主-病毒相互作用提供新的见解。