Signatures of immune dysfunction in HIV and HCV infection share features with chronic inflammation in aging and persist after viral reduction or elimination.
Signatures of immune dysfunction in HIV and HCV infection share features with chronic inflammation in aging and persist after viral reduction or elimination.
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DOI：
10.1073/pnas.2022928118
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发表时间：
2021-04-06
影响因子：
11.1
通讯作者：
Furman D
中科院分区：
文献类型：
--
作者：
Lopez Angel CJ;Pham EA;Du H;Vallania F;Fram BJ;Perez K;Nguyen T;Rosenberg-Hasson Y;Ahmed A;Dekker CL;Grant PM;Khatri P;Maecker HT;Glenn JS;Davis MM;Furman D
慢性炎症导致衰老的发病率和死亡率，但感染相关慢性炎症功能障碍的机制是否相似尚不清楚。使用多队列系统免疫学方法，我们确定了在衰老和慢性病毒感染（即HIV和丙型肝炎病毒）中共享的免疫功能障碍的特征。我们发现，尽管病毒清除，这些共享的功能障碍仍然存在，我们描述了在病毒根除过程中发生的功能协调的变化。最后，我们强调随着病毒载量下降，所有主要免疫细胞谱系的干扰素-α敏感性部分恢复。我们的研究结果表明，广泛和持久的功能重塑和人类免疫系统的恶化，尽管消除慢性病原体负担，共享的慢性炎症在老化的特点。慢性炎症被认为是衰老中发病率和死亡率的主要原因，但感染相关慢性炎症中功能障碍的机制是否相似尚不清楚。在这里，我们分析了一组老年人与一组长期抗逆转录病毒治疗的HIV患者或丙型肝炎病毒（HCV）患者在索非布韦治疗前后的免疫蛋白质组、细胞组成和信号状态。我们发现了衰老相关和感染相关慢性炎症的共同改变，包括T细胞记忆膨胀，炎症细胞内信号传导途径的上调，以及淋巴细胞和骨髓细胞对细胞因子的敏感性降低。在HIV组群中，尽管病毒抑制超过10年，这些失调仍很明显。HCV队列中的病毒清除部分恢复了细胞对干扰素-α的敏感性，但许多免疫系统改变持续至少1年治疗后。我们的研究结果表明，在HIV和HCV队列中，免疫系统的广泛重塑和退化可以持续一年或更长时间，即使在去除或大幅减少病原体负荷之后，这也具有衰老中慢性炎症的一些特征。
Chronic inflammation contributes to morbidity and mortality in aging, but whether similar mechanisms underlie dysfunction in infection-associated chronic inflammation is unclear. Using a multicohort systems immunology approach, we identified signatures of immune dysfunction that are shared in aging and chronic viral infections, namely HIV and hepatitis C virus. We show that these shared dysfunctions persist despite viral clearance, and we describe the changes in functional coordination that occur during viral eradication. Finally, we highlight a partial restoration in interferon-α sensitivity across all major immune cell lineages as viral load drops. Our findings suggest a broad and persistent functional remodeling and deterioration of the human immune system despite removal of a chronic pathogenic burden that shares features of chronic inflammation in aging. Chronic inflammation is thought to be a major cause of morbidity and mortality in aging, but whether similar mechanisms underlie dysfunction in infection-associated chronic inflammation is unclear. Here, we profiled the immune proteome, and cellular composition and signaling states in a cohort of aging individuals versus a set of HIV patients on long-term antiretroviral therapy therapy or hepatitis C virus (HCV) patients before and after sofosbuvir treatment. We found shared alterations in aging-associated and infection-associated chronic inflammation including T cell memory inflation, up-regulation of intracellular signaling pathways of inflammation, and diminished sensitivity to cytokines in lymphocytes and myeloid cells. In the HIV cohort, these dysregulations were evident despite viral suppression for over 10 y. Viral clearance in the HCV cohort partially restored cellular sensitivity to interferon-α, but many immune system alterations persisted for at least 1 y posttreatment. Our findings indicate that in the HIV and HCV cohorts, a broad remodeling and degradation of the immune system can persist for a year or more, even after the removal or drastic reduction of the pathogen load and that this shares some features of chronic inflammation in aging.
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影响因子：
16
作者：
Gross AM;Jaeger PA;Kreisberg JF;Licon K;Jepsen KL;Khosroheidari M;Morsey BM;Swindells S;Shen H;Ng CT;Flagg K;Chen D;Zhang K;Fox HS;Ideker T
通讯作者：
Ideker T
对CD4（+）与CD8（+）T细胞的干扰素γ产生中转录的信号换能器和转录激活因子（Stat）4的谱系特异性需求。
影响因子：
15.3
作者：
Carter, L L;Murphy, K M
通讯作者：
Murphy, K M
影响因子：
64.5
作者：
Brodin P;Jojic V;Gao T;Bhattacharya S;Angel CJ;Furman D;Shen-Orr S;Dekker CL;Swan GE;Butte AJ;Maecker HT;Davis MM
通讯作者：
Davis MM
影响因子：
4.8
作者：
Jacob, A;Cooney, D;Coggeshall, KM
通讯作者：
Coggeshall, KM
DOI：
10.1073/pnas.1617959114
发表时间：
2017-01-31
影响因子：
11.1
作者：
de Bourcy, Charles F. A.;Angel, Cesar J. Lopez;Quake, Stephen R.
通讯作者：
Quake, Stephen R.