Dissecting the effects of filarial-associated immunomodulation on HIV susceptibility

在过去的几十年里，艾滋病病毒在撒哈拉以南非洲的迅速传播导致了不同的假说来解释这一现象。一个众所周知的假设认为，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，从而增加对艾滋病毒的易感性。在坦桑尼亚最近的一项前瞻性研究中，我们的联盟首次证明，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岁的人群中。已知LF可诱导宿主的免疫调节，该联盟的初步研究结果表明，LF感染的个体活化CD4+ T细胞的频率增加，而CD8+ T细胞表现出衰竭的标记。有趣的是，耗尽的CD8+ T细胞仅在具有外周微丝蚴（MF）的个体中发现，即蠕虫的后代。本研究将继续调查加纳和坦桑尼亚流行地区LF和HIV的免疫流行病学关联。首先，对同一坦桑尼亚队列进行的一项后续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才应用，我们处于一个独特的位置来解决这个问题，而且，以纵向方式破译该队列的免疫学变化。在加纳进行的进一步实地研究将评估艾滋病毒在慢性丝虫病和盘尾丝虫病流行地区的流行情况，从而提供关于易感性增加是仅限于慢性丝虫病感染还是丝虫病本身现象的信息。此外，通过将lf感染个体细分为感染状态（MF+ vs. MF-），我们将确定所观察到的关联是否依赖于MF，此外，通过免疫谱分析，我们将获得丝虫病诱导的驱动易感性增强的机制的新见解。最后，利用转基因HSA-HIV毒株和来自不同菌种的抗原体外刺激PBMC，分析不同感染情况下的免疫反应。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。

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.