Foreman Taylor W, Mehra Smriti, LoBato Denae N, Malek Adel, Alvarez Xavier, Golden Nadia A, Bucşan Allison N, Didier Peter J, Doyle-Meyers Lara A, Russell-Lodrigue Kasi E, Roy Chad J, Blanchard James, Kuroda Marcelo J, Lackner Andrew A, Chan John, Khader Shabaana A, Jacobs William R, Kaushal Deepak
Tulane National Primate Research Center, Covington, LA 70471; Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA 70112;
Tulane National Primate Research Center, Covington, LA 70471; Center for Biomedical Research Excellence, Louisiana State University School of Veterinary Medicine, Baton Rouge, LA 70803; Department of Pathobiological Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, LA 70803;
Proc Natl Acad Sci U S A. 2016 Sep 20;113(38):E5636-44. doi: 10.1073/pnas.1611987113. Epub 2016 Sep 6.
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.
结核分枝杆菌（Mtb）与人类免疫缺陷病毒（HIV）在合并感染患者中的协同作用，因结核病（TB）和艾滋病对全球死亡率产生了深远影响。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发生率，CD4(+) T细胞数量下降被认为是主要原因。在本研究中，非人灵长类动物同时感染了Mtb和猿猴免疫缺陷病毒（SIV），模拟人类合并感染情况。大多数动物表现出Mtb复制的快速重新激活，进而发展为播散性结核病，并增加了与SIV相关的病理变化。尽管在所有合并感染的猕猴中均观察到肺部CD4(+) T细胞严重缺失，但仍有一部分动物能够预防重新激活并维持LTBI。对该队列动物的肺部免疫反应和病理情况进行研究表明，CD8(+) 记忆T细胞增殖增加、颗粒酶B产生增多以及B细胞滤泡扩大与预防重新激活相关。我们的研究结果揭示了控制与SIV和TB相关病理变化的机制。这些不依赖CD4的保护性免疫反应值得在能够控制结核感染的HIV合并感染人类中进一步研究。此外，这些发现将为深入了解对Mtb的天然免疫提供见解，并指导新型疫苗策略和免疫疗法的开发。
