HIV Infection Functionally Impairs Mycobacterium tuberculosis-Specific CD4 and CD8 T-Cell Responses
HIV Infection Functionally Impairs Mycobacterium tuberculosis-Specific CD4 and CD8 T-Cell Responses
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DOI：
10.1128/jvi.01728-18
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发表时间：
2019-03-01
影响因子：
5.4
通讯作者：
Perreau, Matthieu
中科院分区：
文献类型：
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作者：
Amelio, Patrizia;Portevin, Damien;Perreau, Matthieu
人类免疫缺陷病毒（HIV）感染是导致结核分枝杆菌从潜伏性结核感染（LTBI）发展为结核病（TB）的主要危险因素。由于长期治疗的病毒血症hiv感染者比未感染hiv的人发生TB的风险更高，我们假设从LTBI到肺结核（PTB）的进展可能不仅是由于CD4 t细胞耗损，而且是由于M. tuberculosis特异性CD4 t细胞功能损伤。为了验证这一假设，研究了未经治疗的坦桑尼亚LTBI （n = 20）或PTB （n = 67）患者中结核分枝杆菌特异性t细胞频率和细胞因子谱，并与未经治疗的结核分枝杆菌/ hiv合并感染的LTBI （n = 15）或PTB （n = 10）患者进行了比较。我们发现HIV感染显著降低了LTBI或PTB患者中产生M. tuberculosis特异性CD4 T细胞Th2（白细胞介素4 [IL-4]/IL-5/IL-13）和产生M. tuberculosis特异性CD4和CD8 T细胞il -2的比例（P = 0.05）。有趣的是，IL-2产生的缺失与M. tuberculosis特异性CD4和CD8 T细胞上PD-1表达的显著增加相关（P = 0.05），而Th2细胞因子产生的缺失与记忆性CD4 T细胞中Gata-3表达的显著降低相关（P = 0.05）。最后，我们发现结核分枝杆菌/艾滋病合并结核分枝杆菌患者的血清IL-1 =、IL-6、c反应蛋白（CRP）、IL-23和IP-10水平显著低于HIV阴性结核分枝杆菌患者（P = 0.05），表明HIV感染显著抑制结核分枝杆菌诱导的全身促炎细胞因子反应。综上所述，这项研究表明，除了消耗结核分枝杆菌特异性CD4 T细胞外，HIV感染还显著损害了坦桑尼亚LTBI或PTB患者功能上有利的结核分枝杆菌特异性CD4 T细胞反应。结核分枝杆菌和人类免疫缺陷病毒（HIV）感染在世界几个地区共流行，结核分枝杆菌/艾滋病毒感染者更容易发展为结核病。因此，我们假设HIV感染可能会损害潜伏性结核感染（LTBI）或活动性肺结核（PTB）患者的结核分枝杆菌特异性保护性免疫。在这项研究中，我们证明结核分枝杆菌/ hiv合并感染的个体具有较少的循环结核分枝杆菌特异性CD4 T细胞，并且那些在LTBI和PTB环境中仍然存在功能受损的CD4 T细胞。此外，我们发现HIV感染显著干扰M. tuberculosis诱导的全身促炎细胞因子/
Human immunodeficiency virus (HIV) infection is the major risk factor predisposing for Mycobacterium tuberculosis progression from latent tuberculosis infection (LTBI) to tuberculosis disease (TB). Since long-term-treated aviremic HIVinfected individuals remained at higher risk of developing TB than HIV-uninfected individuals, we hypothesized that progression from LTBI to pulmonary TB (PTB) might be due not only to CD4 T-cell depletion but also to M. tuberculosis-specific CD4 T-cell functional impairment. To test this hypothesis, M. tuberculosis-specific T-cell frequencies and cytokine profiles were investigated in untreated Tanzanian individuals suffering from LTBI (n = 20) or PTB (n = 67) and compared to those of untreated M. tuberculosis/HIV-coinfected individuals suffering from LTBI (n = 15) or PTB (n = 10). We showed that HIV infection significantly reduced the proportion of Th2 (interleukin 4 [IL-4]/IL-5/IL-13) producing M. tuberculosis-specific CD4 T cells and IL-2producing M. tuberculosis-specific CD4 and CD8 T cells in individuals with LTBI or PTB (P = 0.05). Interestingly, the loss of IL-2 production was associated with a significant increase of PD-1 expression on M. tuberculosis-specific CD4 and CD8 T cells (P = 0.05), while the loss of Th2 cytokine production was associated with a significant reduction of Gata-3 expression in memory CD4 T cells (P = 0.05). Finally, we showed that the serum levels of IL-1 =, IL-6, C-reactive protein (CRP), IL-23, and IP-10 were significantly reduced in M. tuberculosis/HIV-coinfected individuals with PTB compared to those in HIV-negative individuals with PTB (P = 0.05), suggesting that HIV infection significantly suppresses M. tuberculosis-induced systemic proinflammatory cytokine responses. Taken together, this study suggests that in addition to depleting M. tuberculosis-specific CD4 T cells, HIV infection significantly impairs functionally favorable M. tuberculosis-specific CD4 T-cell responses in Tanzanian individuals with LTBI or PTB.IMPORTANCE Mycobacterium tuberculosis and human immunodeficiency virus (HIV) infections are coendemic in several regions of the world, and M. tuberculosis/HIVcoinfected individuals are more susceptible to progression to tuberculosis disease. We therefore hypothesized that HIV infection would potentially impair M. tuberculosis-specific protective immunity in individuals suffering from latent tuberculosis infection (LTBI) or active pulmonary tuberculosis (PTB). In this study, we demonstrated that M. tuberculosis/HIV-coinfected individuals have fewer circulating M. tuberculosis-specific CD4 T cells and that those that remained were functionally impaired in both LTBI and PTB settings. In addition, we showed that HIV infection significantly interferes with M. tuberculosis-induced systemic proinflammatory cytokine/