Lee Madeline J, Litchford Morgan L, Vendrame Elena, Vergara Rosemary, Ranganath Thanmayi, Fish Carolyn S, Chebet Daisy, Langat Agnes, Mburu Caren, Neary Jillian, Benki Sarah, Wamalwa Dalton, John-Stewart Grace, Lehman Dara A, Blish Catherine A
Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA; Stanford Immunology Program, Stanford University School of Medicine, Stanford, CA, USA.
Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Virology. 2025 Jan;602:110318. doi: 10.1016/j.virol.2024.110318. Epub 2024 Nov 26.
Timely initiation of antiretroviral therapy (ART) remains a major challenge in the effort to treat children living with HIV ("CLH") and little is known regarding the dynamics of immune normalization following ART in CLH with varying times to and durations of ART. Here, we leveraged two cohorts of virally-suppressed CLH from Nairobi, Kenya to examine differences in the peripheral immune systems between two cohorts of age-matched children (to control for immune changes with age): one group which initiated ART during early HIV infection and had been on ART for 5-6 years at evaluation (early, long-term treated; "ELT" cohort), and one group which initiated ART later and had been on ART for approximately 9 months at evaluation (delayed, short-term treated; "DST" cohort). We profiled PBMC and purified NK cells from these two cohorts by mass cytometry time-of-flight (CyTOF). Although both groups of CLH had undetectable viral RNA load at evaluation, there were marked differences in both immune composition and immune phenotype between the ELT cohort and the DST cohort. DST donors had reduced CD4 T cell percentages, decreased naive to effector memory T cell ratios, and markedly higher expression of stress-induced markers. Conversely, ELT donors had higher naive to effector memory T cell ratios, low expression of stress-induced markers, and increased expression of markers associated with an effective antiviral response and resolution of inflammation. Collectively, our results demonstrate key differences in the immune systems of virally-suppressed CLH with different ages at ART initiation and durations of treatment and provide further rationale for emphasizing early onset of ART.
及时启动抗逆转录病毒疗法（ART）仍然是治疗感染艾滋病毒儿童（“CLH”）的一项重大挑战，对于不同ART启动时间和治疗时长的CLH在接受ART后免疫恢复正常的动态变化，我们了解甚少。在此，我们利用来自肯尼亚内罗毕的两组病毒得到抑制的CLH队列，来研究两组年龄匹配儿童（以控制年龄导致的免疫变化）外周免疫系统的差异：一组在早期艾滋病毒感染期间启动ART，在评估时已接受ART治疗5 - 6年（早期、长期接受治疗；“ELT”队列），另一组较晚启动ART，在评估时已接受ART治疗约9个月（延迟、短期接受治疗；“DST”队列）。我们通过飞行时间质谱流式细胞术（CyTOF）对这两组队列的外周血单核细胞（PBMC）和纯化的自然杀伤（NK）细胞进行了分析。尽管两组CLH在评估时病毒RNA载量均检测不到，但ELT队列和DST队列在免疫组成和免疫表型方面存在显著差异。DST组供体的CD4 T细胞百分比降低，初始T细胞与效应记忆T细胞的比例下降，应激诱导标志物的表达明显更高。相反，ELT组供体的初始T细胞与效应记忆T细胞的比例更高，应激诱导标志物的表达较低，与有效抗病毒反应和炎症消退相关的标志物表达增加。总体而言，我们的结果表明，不同ART启动年龄和治疗时长的病毒得到抑制的CLH免疫系统存在关键差异，并为强调早期启动ART提供了进一步的理论依据。
