Prodger J L, Hirbod T, Kigozi G, Nalugoda F, Reynolds S J, Galiwango R, Shahabi K, Serwadda D, Wawer M J, Gray R H, Kaul R
Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
Department of Medicine, Solna, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
Mucosal Immunol. 2014 May;7(3):634-44. doi: 10.1038/mi.2013.83. Epub 2013 Oct 23.
Human immunodeficiency virus (HIV) susceptibility is heterogenous, with some HIV-exposed but seronegative (HESN) individuals remaining uninfected despite repeated exposure. Previous studies in the cervix have shown that reduced HIV susceptibility may be mediated by immune alterations in the genital mucosa. However, immune correlates of HIV exposure without infection have not been investigated in the foreskin. We collected sub-preputial swabs and foreskin tissue from HESN (n=20) and unexposed control (n=57) men undergoing elective circumcision. Blinded investigators assayed swabs for HIV-neutralizing IgA, innate antimicrobial peptides, and cytokine levels. Functional T-cell subsets from foreskin tissue were assessed by flow cytometry. HESN foreskins had elevated α-defensins (3,027 vs. 1,795 pg ml(-1), P=0.011) and HIV-neutralizing IgA (50.0 vs. 13.5% of men, P=0.019). Foreskin tissue from HESN men contained a higher density of CD3 T cells (151.9 vs. 69.9 cells mm(-2), P=0.018), but a lower proportion of these was Th17 cells (6.12 vs. 8.04% of CD4 T cells, P=0.007), and fewer produced tumor necrosis factor α (TNFα) (34.3 vs. 41.8% of CD4 T cells, P=0.037; 36.9 vs. 45.7% of CD8 T cells, P=0.004). A decrease in the relative abundance of susceptible CD4 T cells and local TNFα production, in combination with HIV-neutralizing IgA and α-defensins, may represent a protective immune milieu at a site of HIV exposure.
人类免疫缺陷病毒（HIV）易感性存在异质性，一些暴露于HIV但血清学阴性（HESN）的个体尽管反复接触却仍未感染。先前在宫颈的研究表明，HIV易感性降低可能由生殖器黏膜的免疫改变介导。然而，包皮中未感染HIV的暴露免疫相关性尚未得到研究。我们收集了接受择期包皮环切术的HESN男性（n = 20）和未暴露对照男性（n = 57）的包皮下拭子和包皮组织。不知情的研究人员检测了拭子中的HIV中和IgA、先天性抗菌肽和细胞因子水平。通过流式细胞术评估包皮组织中的功能性T细胞亚群。HESN包皮中的α-防御素水平升高（3,027 vs. 1,795 pg/ml，P = 0.011），HIV中和IgA水平也升高（男性比例为50.0% vs. 13.5%，P = 0.019）。HESN男性的包皮组织中CD3 T细胞密度更高（151.9 vs. 69.9 个细胞/mm²，P = 0.018），但其中Th17细胞的比例较低（占CD4 T细胞的6.12% vs. 8.04%，P = 0.007），产生肿瘤坏死因子α（TNFα）的细胞也较少（占CD4 T细胞的34.3% vs. 41.8%，P = 0.037；占CD8 T细胞的36.9% vs. 45.7%，P = 0.004）。易感CD4 T细胞相对丰度的降低和局部TNFα的产生，与HIV中和IgA和α-防御素相结合，可能代表了HIV暴露部位的一种保护性免疫环境。
