Seminal Plasma-Derived Extracellular-Vesicle Fractions from HIV-Infected Men Exhibit Unique MicroRNA Signatures and Induce a Proinflammatory Response in Cells Isolated from the Female Reproductive Tract

The continuing spread of HIV/AIDS is predominantly fueled by sexual exposure to HIV-contaminated semen. Seminal plasma (SP), the liquid portion of semen, harbors a variety of factors that may favor HIV transmission by facilitating viral entry into host cells, eliciting the production of pro-inflammatory cytokines, and enhancing the translocation of HIV across the genital epithelium. One important and abundant class of factors in SP is extracellular vesicles (EVs), which in general are important intercellular signal transducers. Although numerous studies have characterized blood plasma-derived EVs from both uninfected and HIV-infected individuals, little is known about the properties of EVs from semen of HIV-infected individuals. We report here that fractionated SP enriched for EVs from HIV-infected men induce potent transcriptional responses in epithelial and stromal cells that interface with luminal contents of the female reproductive tract. Compared to semen EV fractions from uninfected individuals, those from acutely-infected individuals induced a more pro-inflammatory signature. This was not associated with any observable differences in the surface phenotypes of the vesicles. However, miRNA expression profiling analysis revealed that EV fractions from infected individuals exhibit a broader and more diverse profile. Taken together, our data suggest that SP EVs from HIV-infected individuals exhibit unique miRNA signatures and exert potent pro-inflammatory transcriptional changes in cells of the female reproductive tract, which may facilitate HIV transmission. Overall design: The seminal plasma-derived microvesicle fractions (from 15 acutely-infected individuals and from 15 uninfected individuals) were assessed for their effects on endometrial stromal fibroblasts (n=3 donors) and endometrial epithelial cells (n=3 donors) by RNAseq.

人类免疫缺陷病毒/获得性免疫缺陷综合征（HIV/AIDS）的持续传播，主要源于性接触被HIV污染的精液。精液浆（seminal plasma, SP）即精液的液态组分，含有多种可促进HIV传播的因子：包括协助病毒侵入宿主细胞、诱导促炎细胞因子产生，以及增强HIV穿过生殖道上皮的转位能力。精液浆中一类重要且含量丰富的因子为细胞外囊泡（extracellular vesicles, EVs），这类囊泡通常是关键的细胞间信号转导介质。尽管已有多项研究对未感染及HIV感染者的血浆来源EVs进行了表征，但目前对HIV感染者精液来源EVs的特性仍知之甚少。本研究发现，从HIV感染男性精液中分离富集的EV组分，可在与女性生殖道腔内容物直接接触的上皮细胞及基质细胞中诱导强烈的转录应答。与未感染个体的精液EV组分相比，急性HIV感染者的EV组分可诱导更强的促炎基因表达特征，且该差异未伴随囊泡表面表型的可观测变化。然而，miRNA表达谱分析显示，感染个体的EV组分展现出更广泛且多样的表达谱。综上，本研究数据表明，HIV感染者的精液浆EVs具有独特的miRNA特征，并可在女性生殖道细胞中诱导强烈的促炎转录变化，这可能促进HIV的传播。总体实验设计：本研究通过RNA测序（RNAseq），评估了来自15名急性HIV感染者及15名未感染个体的精液浆来源微囊泡组分，对子宫内膜基质成纤维细胞（n=3名供体）及子宫内膜上皮细胞（n=3名供体）的影响。