CD4+ T-cell-independent mechanisms suppress reactivation of latent tuberculosis in a macaque model of HIV coinfection
CD4+ T-cell-independent mechanisms suppress reactivation of latent tuberculosis in a macaque model of HIV coinfection
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DOI：
10.1073/pnas.1611987113
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发表时间：
2016-09-20
影响因子：
11.1
通讯作者：
Kaushal, Deepak
中科院分区：
文献类型：
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作者：
Foreman, Taylor W.;Mehra, Smriti;Kaushal, Deepak
结核分枝杆菌（Mtb）和艾滋病毒在合并感染患者中的协同作用深刻影响了结核病（TB）和艾滋病导致的全球死亡率。HIV显著增加了潜伏性结核感染（LTBI）重新激活为活动性疾病的比率，CD4（+）T细胞的下降被认为是主要的因果关系。在这项研究中，非人灵长类动物共感染结核分枝杆菌和猿猴免疫缺陷病毒（SIV），重现人类共感染。大多数动物表现出Mtb复制的快速再激活，进展为播散性TB和增加的SIV相关病理。尽管在所有共感染的猕猴中观察到肺CD4（+）T细胞的严重损失，但动物的亚群仍然能够防止再活化并维持LTBI。对该队列中肺免疫应答和病理学的研究表明，增加的CD8（+）记忆T细胞增殖、较高的颗粒酶B产生和扩大的B细胞滤泡与防止再活化相关。我们的研究结果揭示了控制SIV和TB相关病理的机制。这些不依赖于CD4的保护性免疫应答保证了在能够控制其TB感染的HIV共感染者中的进一步研究。此外，这些发现将提供对Mtb天然免疫的深入了解，并将指导新疫苗策略和免疫疗法的开发。
The synergy between Mycobacterium tuberculosis (Mtb) and HIV in coinfected patients has profoundly impacted global mortality because of tuberculosis (TB) and AIDS. HIV significantly increases rates of reactivation of latent TB infection (LTBI) to active disease, with the decline in CD4(+) T cells believed to be the major causality. In this study, nonhuman primates were coinfected with Mtb and simian immunodeficiency virus (SIV), recapitulating human coinfection. A majority of animals exhibited rapid reactivation of Mtb replication, progressing to disseminated TB and increased SIV-associated pathology. Although a severe loss of pulmonary CD4(+) T cells was observed in all coinfected macaques, a subpopulation of the animals was still able to prevent reactivation and maintain LTBI. Investigation of pulmonary immune responses and pathology in this cohort demonstrated that increased CD8(+) memory T-cell proliferation, higher granzyme B production, and expanded B-cell follicles correlated with protection from reactivation. Our findings reveal mechanisms that control SIV- and TB-associated pathology. These CD4-independent protective immune responses warrant further studies in HIV coinfected humans able to control their TB infection. Moreover, these findings will provide insight into natural immunity to Mtb and will guide development of novel vaccine strategies and immunotherapies.