Vom Steeg Landon G, Shen Zheng, Collins Jane, Patel Mickey V, Barr Fiona D, Hopkins Daniel C, Ochsenbauer Christina, Wira Charles R
Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH, United States.
Department of Medicine, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States.
Front Immunol. 2025 Jan 13;15:1506653. doi: 10.3389/fimmu.2024.1506653. eCollection 2024.
Epidemiological evidence suggests that post-menopausal women are more susceptible to HIV infection following sexual intercourse than are younger cohorts for reasons that remain unclear. Here, we evaluated how menopause-associated changes in CD4 T cell numbers and subsets as well as HIV coreceptor expression, particularly CCR5, in the endometrium (EM), endocervix (CX), and ectocervix (ECX) may alter HIV infection susceptibility. Using a tissue-specific mixed cell infection model, we demonstrate that while no changes in CD14 macrophage infection susceptibility were observed, CD4 T cell HIV-1 infection frequency increases following menopause in the EM, but not CX nor ECX. Unexpectedly, the CD4 T cell expression of two known correlates of HIV infection susceptibly, CCR5 and integrin-α4β7, increased following menopause across all three tissues despite only being associated with increased infection frequency in EM derived CD4 T cells. After controlling for changes in the expression of either receptor, both CCR5 and α4β7 expressing CD4 T cells isolated from the EM of post-menopausal women remained more susceptible to HIV-1 infection than those isolated from pre-menopausal women. Shifts in T helper subset composition, including increases in Th1 frequency and decreases in Th17 and Treg frequency were also observed in the EM only following menopause, but did not correlate with increased infection frequency. Treatment of EM derived CD4 T cells with 17β-estradiol (E) prior to viral infection, reduced infection frequency independent of changes in either CCR5 or α4β7 expression frequency. Our results demonstrate that the susceptibility of EM derived CD4 T cells to HIV-1 infection increases post menopause but is unlikely to be driven by increased expression frequency of either CCR5 or integrin-α4β7. These findings contribute to our understanding of how advanced age alters HIV infection risk which will become increasingly important as the human population continues to age.
流行病学证据表明，绝经后女性在性交后比年轻人群更容易感染艾滋病毒，原因尚不清楚。在此，我们评估了绝经相关的子宫内膜（EM）、子宫颈内膜（CX）和子宫颈外膜（ECX）中CD4 T细胞数量和亚群的变化以及艾滋病毒共受体表达，特别是CCR5的表达变化，如何改变艾滋病毒感染易感性。使用组织特异性混合细胞感染模型，我们证明，虽然未观察到CD14巨噬细胞感染易感性的变化，但绝经后EM中CD4 T细胞的HIV-1感染频率增加，而CX和ECX中则没有。出乎意料的是，尽管艾滋病毒感染易感性的两个已知相关因素CCR5和整合素-α4β7的CD4 T细胞表达仅与EM来源的CD4 T细胞中增加的感染频率相关，但绝经后在所有三个组织中均增加。在控制任一受体表达的变化后，从绝经后女性的EM中分离出的表达CCR5和α4β7的CD4 T细胞仍然比从绝经前女性中分离出的细胞更容易感染HIV-1。仅在绝经后EM中也观察到辅助性T细胞亚群组成的变化，包括Th1频率增加以及Th17和Treg频率降低，但与增加的感染频率无关。在病毒感染前用17β-雌二醇（E）处理EM来源的CD4 T细胞，可降低感染频率，而与CCR5或α4β7表达频率的变化无关。我们的结果表明，EM来源的CD4 T细胞对HIV-1感染的易感性在绝经后增加，但不太可能由CCR5或整合素-α4β7表达频率的增加驱动。这些发现有助于我们理解老年如何改变艾滋病毒感染风险，随着人口持续老龄化，这将变得越来越重要。
