Mataramvura Hope, Jӓger Julia, Jordan-Paiz Ana, Mazengera Lovemore Ronald, Gumbo Felicity Zvanyadza, Bunders Madeleine J, Duri Kerina
Immunology Unit, Department of Laboratory Diagnostic and Investigative Sciences, Faculty of Medicine and Health Sciences, University of Zimbabwe, UZ-FMHS), Harare, Zimbabwe.
Department of Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany.
BMC Immunol. 2024 Dec 19;25(1):82. doi: 10.1186/s12865-024-00674-4.
HIV-exposed uninfected (HEU) children are at increased risk of morbidity during the first years of life. Although the immune responses of HEU infants in early-life are relatively well described, studies of natural killer (NK) cells in older HEU children are lacking. NK cell subsets were analysed in HEU children and compared to those in HIV unexposed uninfected (HUU) children aged ~ five years.
Multi-parametric flow cytometry was used to characterize peripheral blood-derived NK cell CD56, CD16, CD57, NKG2A and KIR3DL1/KIR2DL2/L3 expression, including intracellular perforin and granzyme B. NK cell subsets were compared between HEU children exposed to prenatal antiretroviral therapy (ART) from conception [long-term (HEULT)]; those exposed to ART during pregnancy [medium-term (HEUMT)] with continued exposure throughout the breastfeeding period and HUU peers. Furthermore, clinical data of the children, including sick clinic visits and hospitalizations documented in morbidity diaries from birth to 5 years were compared between HEU and HUU groups. Frequencies of CD56 and CD56 NK cell were correlated with these clinical parameters.
139 children were enrolled however, 133 comprising 43 HEULT, 38 HEUMT and 52 HUU were included in the main analyses. Total NK cell, CD56 nor CD56 NK cell proportions differed between HEU and HUU children. However, HEULT children had lower frequencies of CD56 NK cells compared to HEUMT children, (p = 0.002) which maintained significance after controlling for preterm birth, p = 0.012. No differences were observed between HEULT and HUU. The expressions of NKG2A, KIR3DL1/KIR2DL2/L3 and CD57 on CD56 and CD56 NK cells were similar between the three groups. Furthermore, the frequencies of granzyme B and perforin double positive NK cells were similar between the HUU with HEULT and HEUMT children. CD56 NK cell counts had a significant moderate negative correlation with recurrent respiratory infections (rho=-0.38; p = 0.010) in HUU children and negatively correlated with total sick clinic visits in HEUMT (rho=-0.40, p = 0.064).
The proportions of total NK cell, CD56 and CD56 NK cells, NK cells inhibitory and differentiation surface marker expression and cytolytic granule-positive cells were similar between HEU and HUU children. These data suggest that early-life HIV/ART exposure may not result in major changes in NK cell subsets at 5 years of age.
暴露于HIV但未感染（HEU）的儿童在生命的最初几年发病风险增加。虽然HEU婴儿早期的免疫反应已有相对充分的描述，但关于大龄HEU儿童自然杀伤（NK）细胞的研究尚缺。对HEU儿童的NK细胞亚群进行了分析，并与年龄约5岁的未暴露于HIV且未感染（HUU）的儿童进行比较。
采用多参数流式细胞术对来源于外周血的NK细胞的CD56、CD16、CD57、NKG2A和KIR3DL1/KIR2DL2/L3表达进行表征，包括细胞内穿孔素和颗粒酶B。比较了从受孕开始接受产前抗逆转录病毒治疗（ART）的HEU儿童[长期（HEULT）]；孕期接受ART治疗[中期（HEUMT）]且在整个母乳喂养期持续接受治疗的儿童与HUU儿童。此外，比较了HEU组和HUU组儿童的临床数据，包括从出生到5岁发病日记中记录的门诊就诊和住院情况。CD56和CD56⁺NK细胞的频率与这些临床参数相关。
共纳入139名儿童，然而，主要分析纳入了133名儿童，包括43名HEULT儿童、38名HEUMT儿童和52名HUU儿童。HEU儿童和HUU儿童的总NK细胞、CD56⁻和CD56⁺NK细胞比例无差异。然而，与HEUMT儿童相比，HEULT儿童的CD56⁺NK细胞频率较低（p = 0.002），在控制早产因素后该差异仍具有统计学意义，p = 0.012。HEULT儿童和HUU儿童之间未观察到差异。三组中CD56⁻和CD56⁺NK细胞上NKG2A、KIR3DL1/KIR2DL2/L3和CD57的表达相似。此外，HUU儿童与HEULT和HEUMT儿童中颗粒酶B和穿孔素双阳性NK细胞的频率相似。在HUU儿童中，CD56⁺NK细胞计数与反复呼吸道感染呈显著中度负相关（rho = -0.38；p = 0.010），在HEUMT儿童中与门诊就诊总数呈负相关（rho = -0.40，p = 0.064）。
HEU儿童和HUU儿童在总NK细胞、CD56⁻和CD56⁺NK细胞比例、NK细胞抑制性和分化表面标志物表达以及溶细胞颗粒阳性细胞方面相似。这些数据表明，生命早期暴露于HIV/ART可能不会导致5岁时NK细胞亚群发生重大变化。
