Mucosal Immunology Laboratory, CAPRISA, Durban, KwaZulu-Natal, South Africa.
Africa Health Research Institute (AHRI), Durban, KwaZulu-Natal, South Africa.
J Investig Med. 2021 Jan;69(1):28-40. doi: 10.1136/jim-2020-001424. Epub 2020 Oct 1.
Genital inflammation is an established risk factor for increased HIV acquisition risk. Certain HIV-exposed seronegative populations, who are naturally resistant to HIV infection, have an immune quiescent phenotype defined by reduced immune activation and inflammatory cytokines at the genital tract. Therefore, the aim of this study was to create an immune quiescent environment using immunomodulatory drugs to mitigate HIV infection. Using an peripheral blood mononuclear cell (PBMC) model, we found that inflammation was induced using phytohemagglutinin and Toll-like receptor (TLR) agonists Pam3CSK4 (TLR1/2), lipopolysaccharide (LPS) (TLR4) and R848 (TLR7/8). After treatment with anti-inflammatory drugs, ibuprofen (IBF) and betamethasone (BMS), PBMCs were exposed to HIV NL4-3 AD8. Multiplexed ELISA was used to measure 28 cytokines to assess inflammation. Flow cytometry was used to measure immune activation (CD38, HLA-DR and CCR5) and HIV infection (p24 production) of CD4+ T cells. BMS potently suppressed inflammation (soluble cytokines, p<0.05) and immune activation (CD4+ T cells, p<0.05). BMS significantly reduced HIV infection of CD4+ T cells only in the LPS (0.98%) and unstimulated (1.7%) conditions (p<0.02). In contrast, IBF had minimal anti-inflammatory and immunosuppressive but no anti-HIV effects. BMS demonstrated potent anti-inflammatory effects, regardless of stimulation condition. Despite uniform immunosuppression, BMS differentially affected HIV infection according to the stimulation conditions, highlighting the complex nature of these interactions. Together, these data underscore the importance of interrogating inflammatory signaling pathways to identify novel drug targets to mitigate HIV infection.
生殖器炎症是增加 HIV 获得风险的既定危险因素。某些对 HIV 呈暴露但血清阴性的人群对 HIV 感染具有天然抵抗力，其免疫静止表型的特征是生殖道中免疫激活和炎症细胞因子减少。因此，本研究旨在使用免疫调节药物创造免疫静止环境，以减轻 HIV 感染。我们使用外周血单核细胞（PBMC）模型发现，使用植物血凝素和 Toll 样受体（TLR）激动剂 Pam3CSK4（TLR1/2）、脂多糖（LPS）（TLR4）和 R848（TLR7/8）诱导炎症。在用抗炎药物布洛芬（IBF）和倍他米松（BMS）治疗后，将 PBMC 暴露于 HIV NL4-3 AD8 中。使用多重 ELISA 测量 28 种细胞因子以评估炎症。使用流式细胞术测量 CD4+T 细胞的免疫激活（CD38、HLA-DR 和 CCR5）和 HIV 感染（p24 产生）。BMS 强力抑制炎症（可溶性细胞因子，p<0.05）和免疫激活（CD4+T 细胞，p<0.05）。BMS 仅在 LPS（0.98%）和未刺激（1.7%）条件下显著降低 CD4+T 细胞中的 HIV 感染（p<0.02）。相比之下，IBF 对炎症和免疫抑制的作用极小，但对 HIV 没有影响。BMS 表现出强大的抗炎作用，无论刺激条件如何。尽管具有统一的免疫抑制作用，但 BMS 根据刺激条件对 HIV 感染产生不同的影响，突出了这些相互作用的复杂性。总之，这些数据强调了研究炎症信号通路以确定减轻 HIV 感染的新药物靶点的重要性。
