Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, Washington.
Institute for Human Virology, University of Maryland, Baltimore, Maryland, USA.
AIDS. 2021 Jan 1;35(1):23-32. doi: 10.1097/QAD.0000000000002706.
HIV-exposed uninfected (HEU) infants exhibit altered vaccine responses and an increased mortality compared with HIV-unexposed infants. Here, vaccine responses in HEU and HIV-unexposed cord blood monocytes (CBMs) were assessed following Bacillus Calmette--Guerín (BCG) treatment.
Innate responses to in-vitro BCG treatment were assessed through transcriptional profiling using CBMs obtained from a Nigerian cohort of HIV-infected and uninfected women.
HIV-unexposed (n = 9) and HEU (n = 10) infant CBMs were treated with BCG and transcriptionally profiled with the Nanostring nCounter platform. Differential expression and pathway enrichment analyses were performed, and transcripts were identified with enhanced or dampened BCG responses.
Following BCG stimulation, several pathways associated with inflammatory gene expression were upregulated irrespective of HIV exposure status. Both HIV-unexposed and HEU monocytes increased expression of several cytokines characteristic of innate BCG responses, including IL1β, TNFα, and IL-6. Using differential expression analysis, we identified genes significantly upregulated in HEU compared with HIV-unexposed monocytes including monocyte chemokine CCL7 and anti-inflammatory cytokine TNFAIP6. In contrast, genes significantly upregulated in HIV-unexposed compared with HEU monocytes include chemokine CCL3 and cytokine IL23A, both of which influence anti-mycobacterial T-cell responses. Finally, two genes, which regulate prostaglandin production, CSF2 and PTGS2, were also more significantly upregulated in the HIV-unexposed cord blood indicating that inflammatory mediators are suppressed in the HEU infants.
HEU monocytes exhibit altered induction of several key innate immune responses, providing mechanistic insights into dysregulated innate response pathways that can be therapeutically targeted to improve vaccine responses in HEU infants.
与未暴露于 HIV 的婴儿相比，HIV 暴露未感染（HEU）婴儿的疫苗反应发生改变，死亡率增加。本研究评估了 HIV 感染和未感染妇女的尼日利亚队列婴儿脐带血单核细胞（CBM）中，卡介苗（BCG）治疗后 HEU 和未暴露于 HIV 的 CBM 的疫苗反应。
通过使用从 HIV 感染和未感染妇女的尼日利亚队列中获得的 CBM，通过转录谱评估对体外 BCG 治疗的先天反应。
用 BCG 处理未暴露于 HIV（n=9）和 HEU（n=10）婴儿的 CBM，并使用 Nanostring nCounter 平台进行转录谱分析。进行差异表达和途径富集分析，并确定对 BCG 反应增强或减弱的转录本。
BCG 刺激后，与 HIV 暴露状态无关，几种与炎症基因表达相关的途径均上调。未暴露于 HIV 的单核细胞和 HEU 单核细胞均增加了几种先天 BCG 反应特征性细胞因子的表达，包括 IL1β、TNFα 和 IL-6。使用差异表达分析，我们确定了与未暴露于 HIV 的单核细胞相比，HEU 单核细胞中显著上调的基因，包括单核细胞趋化因子 CCL7 和抗炎细胞因子 TNFAIP6。相反，与 HEU 相比，未暴露于 HIV 的单核细胞中显著上调的基因包括趋化因子 CCL3 和细胞因子 IL23A，这两者均影响抗分枝杆菌 T 细胞反应。最后，两个调节前列腺素产生的基因 CSF2 和 PTGS2 在未暴露于 HIV 的脐带血中也被显著上调，这表明 HEU 婴儿中的炎症介质受到抑制。
HEU 单核细胞表现出几种关键先天免疫反应的改变诱导，为失调的先天反应途径提供了机制见解，这些途径可以通过治疗靶向来改善 HEU 婴儿的疫苗反应。
