Section of Oncology and Immunology, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.
Hospital Universitario 12 de Octubre, Madrid, Spain.
J Int AIDS Soc. 2021 Nov;24(11):e25847. doi: 10.1002/jia2.25847.
Persistence of HIV-1, causing chronic immune activation, is a key determinant of premature senescence. Early antiretroviral therapy (ART) has been associated with a reduced HIV-1 reservoir in children with perinatally acquired HIV-1 (PHIV), but its impact on the senescence process is an open question. We investigated the association between HIV-1 reservoir and biological and immune ageing profile in PHIV enrolled in the multicentre cross-sectional study CARMA (Child and Adolescent Reservoir Measurements on early suppressive ART) conducted within the EPIICAL (Early treated Perinatally HIV Infected individuals: Improving Children's Actual Life) consortium.
Between September 2017 and June 2018, CARMA enrolled 40 PHIV who started ART before 2 years of age and had undetectable viremia for at least 5 years before sampling date. Samples from 37 children with a median age of 13.8 years were available for this study. HIV-1 DNA copies on CD4 cells, relative telomere length (marker of cellular senescence) and levels of T-cell receptor rearrangement excision circle (TREC, marker of thymic output) on CD4 and CD8 cells were quantified by qPCR. Immunological profile was assessed by flow cytometry. Associations between molecular and phenotypic markers, HIV-1 reservoir and age at ART initiation were explored using a multivariable Poisson regression.
Higher HIV-1 reservoir was associated (p<0.001) with telomere shortening (incidence rate ratio [IRR] = 0.15 [0.13-0.17]), immunosenescence (CD28 CD57 , IRR = 1.23 [1.21-1.26]) and immunoactivation (CD38 HLADR , IRR = 7.29 [6.58-8.09]) of CD4 cells. Late ART initiation (after 6 months of age) correlated with higher HIV-1 reservoir levels (552 [303-1001] vs. 89 [56-365] copies/10 CD4 cells, p = 0.003) and percentage of CD4 senescent cells (2.89 [1.95-6.31] vs. 1.02 [0.45-2.69, p = 0.047). TREC levels in CD8 cells were inversely associated with HIV-1 reservoir (IRR = 0.77 [0.76-0.79]) and were significantly lower in late treated PHIV (1128 [486-1671] vs. 2278 [1425-3314], p = 0.042).
Later ART initiation is associated with higher HIV-1 reservoir size, which correlates with increased telomere shortening and senescence of CD4 cells. Timing of ART initiation in infancy has long-term consequences on the immune and biological ageing profile of children with perinatally acquired HIV-1.
HIV-1 的持续存在导致慢性免疫激活，是导致过早衰老的关键决定因素。早期抗逆转录病毒治疗（ART）已与儿童期获得性 HIV-1（PHIV）患者中 HIV-1 储存库减少相关，但它对衰老过程的影响仍是一个悬而未决的问题。我们研究了 HIV-1 储存库与在 EPIICAL（早期治疗围生期 HIV 感染个体：改善儿童实际生活）联盟内进行的多中心横断面研究 CARMA（早期抑制性 ART 下的儿童和青少年储库测量）中入组的 PHIV 的生物学和免疫衰老特征之间的关联。
2017 年 9 月至 2018 年 6 月，CARMA 招募了 40 名在 2 岁之前开始 ART 且在采样前至少 5 年病毒载量不可检测的 PHIV 患者。这项研究中，有 37 名中位年龄为 13.8 岁的儿童有样本可用。通过 qPCR 定量测定 CD4 细胞上的 HIV-1 DNA 拷贝数、相对端粒长度（细胞衰老的标志物）和 CD4 和 CD8 细胞上的 T 细胞受体重组切除环（TREC，胸腺输出的标志物）水平。通过流式细胞术评估免疫表型。使用多变量泊松回归探讨分子和表型标志物、HIV-1 储存库与 ART 起始年龄之间的关联。
更高的 HIV-1 储存库与端粒缩短（发病率比 [IRR] = 0.15 [0.13-0.17]）、免疫衰老（CD28 CD57 ，IRR = 1.23 [1.21-1.26]）和免疫激活（CD38 HLADR ，IRR = 7.29 [6.58-8.09]）相关。晚期 ART 起始（6 个月后）与更高的 HIV-1 储存库水平相关（552 [303-1001] 与 89 [56-365] 拷贝/10 CD4 细胞，p = 0.003）和 CD4 衰老细胞的百分比相关（2.89 [1.95-6.31] 与 1.02 [0.45-2.69，p = 0.047）。CD8 细胞中的 TREC 水平与 HIV-1 储存库呈负相关（IRR = 0.77 [0.76-0.79]），并且在晚期治疗的 PHIV 中显著较低（1128 [486-1671] 与 2278 [1425-3314]，p = 0.042）。
晚期 ART 起始与更高的 HIV-1 储存库大小相关，这与 CD4 细胞的端粒缩短和衰老相关。婴儿期 ART 起始的时间对儿童期获得性 HIV-1 患者的免疫和生物衰老特征具有长期影响。
