Khanolkar Aaruni, Muller William J, Simpson Bridget M, Cerullo Jillian, Williams Ruth, Sowers Sun Bae, Matthews Kiana, Mercader Sara, Hickman Carole J, D'Aquila Richard T, Liu Guorong
Department of Pathology, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL 60611, USA.
Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Commun Med (Lond). 2022;2. doi: 10.1038/s43856-022-00085-9. Epub 2022 Mar 4.
Host-pathogen dynamics associated with HIV infection are quite distinct in children versus adults. We interrogated the functional fitness of the lymphocyte responses in two cohorts of perinatally infected HIV+ pediatric subjects with early anti-retroviral therapy (ART) initiation but divergent patterns of virologic control. We hypothesized that sub-optimal viral control would compromise immune functional fitness.
The immune responses in the two HIV+ cohorts ( = 6 in each cohort) were benchmarked against the responses measured in age-range matched, uninfected healthy control subjects ( = 11) by utilizing tests for normality, and comparison [the Kruskal-Wallis test, and the two-tailed Mann-Whitney test (where appropriate)]. Lymphocyte responses were examined by intra-cellular cytokine secretion, degranulation assays as well as phosflow. A subset of these data were further queried by an automated clustering algorithm. Finally, we evaluated the humoral immune responses to four childhood vaccines in all three cohorts.
We demonstrate that contrary to expectations pediatric HIV+ patients with sub-optimal viral control display no significant deficits in immune functional fitness. In fact, the patients that display better virologic control lack functional Gag-specific T cell responses and compared to healthy controls they display signaling deficits and an enrichment of mitogen-stimulated CD3 negative and positive lymphocyte clusters with suppressed cytokine production.
These results highlight the immune resilience in HIV+ children on ART with sub-optimal viral control. With respect to HIV+ children on ART with better viral control, our data suggest that this cohort might potentially benefit from targeted interventions that might mitigate cell-mediated immune functional quiescence.
与成人相比，儿童HIV感染相关的宿主-病原体动态变化有很大不同。我们研究了两组围产期感染HIV的儿科受试者的淋巴细胞反应功能适应性，这两组受试者均早期开始抗逆转录病毒治疗（ART），但病毒学控制模式不同。我们假设病毒控制欠佳会损害免疫功能适应性。
通过正态性检验和比较（Kruskal-Wallis检验以及在适当情况下的双尾Mann-Whitney检验），将两个HIV+队列（每个队列n = 6）中的免疫反应与年龄匹配的未感染健康对照受试者（n = 11）中测得的反应进行基准比较。通过细胞内细胞因子分泌、脱颗粒试验以及磷酸化流式细胞术检测淋巴细胞反应。这些数据的一个子集通过自动聚类算法进一步查询。最后，我们评估了所有三个队列中对四种儿童疫苗的体液免疫反应。
我们证明，与预期相反，病毒控制欠佳的儿科HIV+患者在免疫功能适应性方面没有明显缺陷。事实上，病毒学控制较好的患者缺乏功能性Gag特异性T细胞反应，与健康对照相比，他们表现出信号传导缺陷，有丝分裂原刺激的CD3阴性和阳性淋巴细胞簇增多且细胞因子产生受抑制。
这些结果突出了病毒控制欠佳的接受ART治疗的HIV+儿童的免疫恢复力。对于病毒控制较好的接受ART治疗的HIV+儿童，我们的数据表明该队列可能会从有针对性的干预措施中获益，这些措施可能会减轻细胞介导的免疫功能静止。
