McMaster Immunology Research Centre, Michael G. DeGroote Centre for Learning and Discovery, McMaster University, Hamilton, Ontario, Canada.
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
Sci Rep. 2017 Nov 10;7(1):15263. doi: 10.1038/s41598-017-15630-z.
Approximately 40% of HIV-1 infections occur in the female genital tract (FGT), primarily through heterosexual transmission. FGT factors determining outcome of HIV-1 exposure are incompletely understood, limiting prevention strategies. Here, humanized NOD-Rag1 γc mice differentially reconstituted with human CD34+ -enriched hematopoietic stem cells (Hu-mice), were used to assess target cell frequency and viral inoculation dose as determinants of HIV-1 infection following intravaginal (IVAG) challenge. Results revealed a significant correlation between HIV-1 susceptibility and hCD45+ target cells in the blood, which correlated with presence of target cells in the FGT, in the absence of local inflammation. HIV-1 plasma load was associated with viral dose at inoculation and frequency of target cells. Events following IVAG HIV-1 infection; viral dissemination and CD4 depletion, were not affected by these parameters. Following IVAG inoculation, HIV-1 titres peaked, then declined in vaginal lavage while plasma showed a reciprocal pattern. The greatest frequency of HIV-1-infected (p24+) cells were found one week post-infection in the FGT versus blood and spleen, suggesting local viral amplification. Five weeks post-infection, HIV-1 disseminated into systemic tissues, in a dose-dependent manner, followed by depletion of hCD45+ CD3+ CD4+ cells. Results indicate target cell frequency in the Hu-mouse FGT is a key determinant of HIV-1 infection, which might provide a useful target for prophylaxis in women.
大约 40%的 HIV-1 感染发生在女性生殖道（FGT），主要通过异性传播。FGT 中决定 HIV-1 暴露结果的因素尚未完全了解，这限制了预防策略的制定。在此，用人源化 NOD-Rag1 γc 小鼠，用富含人 CD34+ 的造血干细胞（Hu-小鼠）进行差异重建，用于评估细胞靶频率和病毒接种剂量作为阴道内（IVAG）挑战后 HIV-1 感染的决定因素。结果表明，HIV-1 易感性与血液中的 hCD45+ 靶细胞显著相关，这与 FGT 中靶细胞的存在相关，而与局部炎症无关。HIV-1 血浆负荷与接种时的病毒剂量和靶细胞的频率有关。阴道内感染 HIV-1 后的事件；病毒传播和 CD4 耗竭，不受这些参数的影响。经 IVAG 接种后，HIV-1 滴度在阴道灌洗液中先达到峰值，然后下降，而血浆则呈现相反的模式。在感染后一周，在 FGT 中发现 HIV-1 感染（p24+）细胞的频率最高，而在血液和脾脏中则较低，提示局部病毒扩增。感染后 5 周，HIV-1 以剂量依赖的方式传播到全身组织，随后 hCD45+ CD3+ CD4+ 细胞耗竭。结果表明，Hu-小鼠 FGT 中的靶细胞频率是 HIV-1 感染的关键决定因素，这可能为女性提供一种有用的预防靶点。
