Division of Pediatrics, University Hospitals Cleveland Medical Center, Cleveland, OH, United States.
Division of Infectious Diseases, Rainbow Babies and Children's Hospital, Cleveland, OH, United States.
Front Immunol. 2023 Mar 28;14:1165964. doi: 10.3389/fimmu.2023.1165964. eCollection 2023.
Perinatally acquired HIV infection (PHIV) occurs during a critical window of immune development. We investigated changes in systemic inflammation and immune activation in adolescents with PHIV and those without HIV (HIV-) in Uganda.
A prospective observational cohort study was performed in 2017-2021 in Uganda. All participants were between 10-18 years of age and without active co-infections. PHIVs were on ART with HIV-1 RNA level ≤400 copies/mL. We measured plasma and cellular markers of monocyte activation, T-cell activation (expression of CD38 and HLA-DR on CD4+ and CD8+), oxidized LDL, markers of gut integrity and fungal translocation. Groups were compared using Wilcoxon rank sum tests. Changes from baseline were examined with 97.5% confidence intervals on relative fold change. P values were adjusted for false discovery rate.
We enrolled 101 PHIV and 96 HIV-; among these, 89 PHIV and 79 HIV- also had measurements at 96 weeks. At baseline, median (Q1, Q3) age was 13 yrs (11,15), and 52% were females. In PHIV, median CD4+ cell counts were 988 cells/µL (638, 1308), ART duration was 10 yrs (8, 11), and 85% had viral load <50 copies/mL throughout the study, 53% of participants had a regimen switch between visits, 85% of whom switched to 3TC, TDF and DTG. Over 96 weeks, while hsCRP decreased by 40% in PHIV (p=0.12), I-FABP and BDG both increased by 19 and 38% respectively (p=0.08 and ≤0.01) and did not change in HIV- (p≥0.33). At baseline, PHIVs had higher monocyte activation (sCD14) (p=0.01) and elevated frequencies of non-classical monocytes (p<0.01) compared to HIV- which remained stable over time in PHIV but increased by 34% and 80% respectively in HIV-. At both time points, PHIVs had higher T cell activation (p ≤ 0.03: CD4+/CD8+ T cells expressing HLA-DR and CD38). Only in PHIV, at both timepoints, oxidized LDL was inversely associated with activated T cells(p<0.01). Switching to dolutegravir at week 96 was significantly associated an elevated level of sCD163 (β=0.4, 95% CI=0.14,0.57, p<0.01), without changes in other markers.
Ugandan PHIV with viral suppression have some improvement in markers of inflammation over time, however T-cell activation remains elevated. Gut integrity and translocation worsened only in PHIV over time. A deeper understanding of the mechanisms causing immune activation in ART treated African PHIV is crucial.
围产期获得性 HIV 感染（PHIV）发生在免疫发育的关键窗口期。我们研究了乌干达 PHIV 青少年和未感染 HIV（HIV-）的青少年全身炎症和免疫激活的变化。
2017-2021 年在乌干达进行了一项前瞻性观察队列研究。所有参与者年龄均在 10-18 岁之间，且无活动性合并感染。PHIV 接受抗逆转录病毒治疗（ART），HIV-1 RNA 水平≤400 拷贝/ml。我们测量了血浆和细胞单核细胞激活标志物、T 细胞激活标志物（CD4+和 CD8+上 CD38 和 HLA-DR 的表达）、氧化型 LDL、肠道完整性和真菌易位标志物。使用 Wilcoxon 秩和检验比较组间差异。使用 97.5%置信区间对相对倍数变化进行基线变化的检验。p 值经假发现率校正。
我们纳入了 101 名 PHIV 和 96 名 HIV-；其中 89 名 PHIV 和 79 名 HIV-在 96 周时也进行了测量。在基线时，中位（Q1，Q3）年龄为 13 岁（11，15），52%为女性。在 PHIV 中，中位 CD4+细胞计数为 988 个/µL（638，1308），ART 持续时间为 10 年（8，11），85%的患者整个研究期间病毒载量<50 拷贝/ml，53%的患者在随访期间更换了治疗方案，其中 85%的患者更换为 3TC、TDF 和 DTG。在 96 周内，尽管 PHIV 中的 hsCRP 降低了 40%（p=0.12），但 I-FABP 和 BDG 分别增加了 19%和 38%（p=0.08 和 p≤0.01），而 HIV-中未发生变化（p≥0.33）。在基线时，PHIV 有更高的单核细胞激活（sCD14）（p=0.01）和非经典单核细胞的频率升高（p<0.01），这一情况在 PHIV 中随时间保持稳定，但在 HIV-中分别增加了 34%和 80%。在两个时间点，PHIV 中 T 细胞激活均更高（p≤0.03：表达 HLA-DR 和 CD38 的 CD4+/CD8+T 细胞）。只有在 PHIV 中，在两个时间点，氧化型 LDL 与活化的 T 细胞呈负相关（p<0.01）。在第 96 周转换为多替拉韦时，sCD163 水平显著升高（β=0.4，95%CI=0.14，0.57，p<0.01），其他标志物无变化。
乌干达 PHIV 病毒抑制后，炎症标志物随时间有所改善，但 T 细胞激活仍升高。肠道完整性和易位仅在 PHIV 中随时间恶化。深入了解导致非洲 PHIV 免疫激活的机制至关重要。
