Abstract

Background

Despite early antiretroviral therapy (ART), ART-suppressed people with human immunodeficiency virus (HIV) (PWH) remain at higher risk for infections and infection-related cancers than the general population. The immunologic pathways that remain abnormal in this setting, potentially contributing to these complications, are unclear.

Methods

ART-suppressed PWH and HIV-negative controls, all cytomegalovirus seropositive and enriched for HIV risk factors, were sampled from an influenza vaccine responsiveness study. PWH were stratified by timing of ART initiation (within 6 months of infection [early ART] vs later) and nadir CD4⁺ T-cell count among later initiators. Between-group differences in kynurenine-tryptophan (KT) ratio, interferon-inducible protein 10, soluble CD14 and CD163, soluble tumor necrosis factor receptor 2, interleukin 6, and soluble urokinase plasminogen activator receptor were assessed after confounder adjustment.

Results

Most participants (92%) were male, reflecting the demographics of early-ART initiators in San Francisco. Most biomarkers were higher among later-ART initiators. Participants in the early-ART group achieved near-normal soluble tumor necrosis factor receptor 2, interleukin 6, and soluble urokinase plasminogen activator receptor levels, but substantially higher KT ratio than those without HIV after confounder adjustment (P = .008). Soluble CD14, soluble CD163, and interferon-inducible protein 10 trended similarly.

Conclusions

While early-ART initiators restore near-normal levels of many inflammatory markers, the kynurenine pathway of tryptophan catabolism remains abnormally high. Because this pathway confers adaptive immune defects and predicts tuberculosis and cancer progression, this it may contribute to persistent risks of these complications in this setting.

中文翻译：

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尽管对人类免疫缺陷病毒进行了非常早期的治疗，但一些免疫激活的生物标志物水平异常

摘要

背景

尽管进行了早期抗逆转录病毒治疗 (ART)，但与普通人群相比，ART 抑制的人类免疫缺陷病毒 (HIV) (PWH) 患者感染和感染相关癌症的风险仍然更高。在这种情况下仍然异常的免疫途径可能导致这些并发症，目前尚不清楚。

方法

ART 抑制的 PWH 和 HIV 阴性对照，所有巨细胞病毒血清阳性且富含 HIV 危险因素，均从流感疫苗反应性研究中取样。PWH 按 ART 开始时间（感染后 6 个月内 [早期 ART] 与较晚）和后期开始者中的最低点 CD4 ⁺ T 细胞计数进行分层。在混杂因素调整后评估犬尿氨酸-色氨酸 (KT) 比值、干扰素诱导蛋白 10、可溶性 CD14 和 CD163、可溶性肿瘤坏死因子受体 2、白细胞介素 6 和可溶性尿激酶纤溶酶原激活物受体的组间差异。

结果

大多数参与者 (92%) 是男性，这反映了旧金山早期 ART 发起者的人口统计数据。大多数生物标志物在后期 ART 发起者中较高。早期 ART 组的参与者实现了接近正常的可溶性肿瘤坏死因子受体 2、白细胞介素 6 和可溶性尿激酶纤溶酶原激活物受体水平，但经过混杂因素调整后，KT 比率显着高于未感染 HIV 的参与者 ( P  = .008)。可溶性 CD14、可溶性 CD163 和干扰素诱导蛋白 10 的趋势相似。

结论

虽然早期 ART 发起者恢复了接近正常水平的许多炎症标志物，但色氨酸分解代谢的犬尿氨酸途径仍然异常高。由于该途径会导致适应性免疫缺陷并预测结核病和癌症进展，因此它可能会导致这些并发症在这种情况下的持续风险。