Franzén Boger Mathias, Hasselrot Tyra, Kaldhusdal Vilde, Miranda Gisele H B, Czarnewski Paulo, Edfeldt Gabriella, Bradley Frideborg, Rexaj Genta, Lajoie Julie, Omollo Kenneth, Kimani Joshua, Fowke Keith R, Broliden Kristina, Tjernlund Annelie
Division of Infectious Diseases, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Center for Molecular Medicine, Stockholm, Sweden.
Division of Computational Science and Technology, KTH Royal Institute of Technology, Stockholm, Sweden.
PLoS Pathog. 2024 Nov 19;20(11):e1012709. doi: 10.1371/journal.ppat.1012709. eCollection 2024 Nov.
Chronic systemic immune activation significantly influences human immunodeficiency virus (HIV) disease progression. Despite evidence of a pro-inflammatory environment in the genital tract of HIV-infected women, comprehensive investigations into cervical tissue from this region remain limited. Similarly, the consequences of chronic HIV infection on the integrity of the female genital epithelium are poorly understood, despite its importance in HIV transmission and replication. Ectocervical biopsies were obtained from HIV-seropositive (n = 14) and HIV-seronegative (n = 47) female Kenyan sex workers. RNA sequencing and bioimage analysis of epithelial junction proteins (E-cadherin, desmoglein-1, claudin-1, and zonula occludens-1) were conducted, along with CD4 staining. RNA sequencing revealed upregulation of immunoregulatory genes in HIV-seropositive women, primarily associated with heightened T cell activity and interferon signaling, which further correlated with plasma viral load. Transcription factor analysis confirmed the upregulation of pro-inflammatory transcription factors, such as RELA, NFKB1, and IKZF3, which facilitates HIV persistence in T cells. Conversely, genes and pathways associated with epithelial barrier function and structure were downregulated in the context of HIV. Digital bioimage analysis corroborated these findings, revealing significant disruption of various epithelial junction proteins in ectocervical tissues of the HIV-seropositive women. Thus, chronic HIV infection associated with ectocervical inflammation, characterized by induced T cell responses and interferon signaling, coupled with epithelial disruption. These alterations may influence HIV transmission and heighten susceptibility to other sexually transmitted infections. These findings prompt exploration of therapeutic interventions to address HIV-related complications and mitigate the risk of sexually transmitted infection transmission.
慢性全身性免疫激活显著影响人类免疫缺陷病毒（HIV）疾病进展。尽管有证据表明HIV感染女性的生殖道存在促炎环境，但对该区域宫颈组织的全面研究仍然有限。同样，尽管慢性HIV感染对女性生殖上皮完整性的影响在HIV传播和复制中很重要，但人们对此了解甚少。从肯尼亚HIV血清阳性（n = 14）和HIV血清阴性（n = 47）的女性性工作者中获取宫颈活检样本。对上皮连接蛋白（E-钙黏蛋白、桥粒芯糖蛋白-1、紧密连接蛋白-1和闭合蛋白-1）进行RNA测序和生物图像分析，并进行CD4染色。RNA测序显示，HIV血清阳性女性的免疫调节基因上调，主要与T细胞活性增强和干扰素信号传导有关，这进一步与血浆病毒载量相关。转录因子分析证实促炎转录因子如RELA、NFKB1和IKZF3上调，这促进了HIV在T细胞中的持续存在。相反，在HIV感染的情况下，与上皮屏障功能和结构相关的基因和通路下调。数字生物图像分析证实了这些发现，揭示了HIV血清阳性女性宫颈外组织中各种上皮连接蛋白的显著破坏。因此，慢性HIV感染与宫颈外炎症相关，其特征为诱导T细胞反应和干扰素信号传导，同时伴有上皮破坏。这些改变可能影响HIV传播并增加对其他性传播感染的易感性。这些发现促使人们探索治疗干预措施，以解决与HIV相关的并发症并降低性传播感染传播的风险。
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