HLA-E-restricted CD8+ T Lymphocytes Efficiently Control Mycobacterium tuberculosis and HIV-1 Coinfection.

HLA-E 限制性 CD8 + T 淋巴细胞有效控制结核分枝杆菌和 HIV-1 共感染。

  • 影响因子:3.37
  • DOI:10.1165/rcmb.2019-0261OC
  • 作者列表:"La Manna MP","Orlando V","Prezzemolo T","Di Carlo P","Cascio A","Delogu G","Poli G","Sullivan LC","Brooks AG","Dieli F","Caccamo N
  • 发表时间:2020-04-01

We investigated the contribution of human leukocyte antigen A2 (HLA-A2) and HLA-E-restricted CD8+ T cells in patients with Mycobacterium tuberculosis and human immunodeficiency virus 1 (HIV-1) coinfection. HIV-1 downregulates HLA-A, -B, and -C molecules in infected cells, thus influencing recognition by HLA class I-restricted CD8+ T cells but not by HLA-E-restricted CD8+ T cells, owing to the inability of the virus to downmodulate their expression. Therefore, antigen-specific HLA-E-restricted CD8+ T cells could play a protective role in Mycobacterium tuberculosis and HIV-1 coinfection. HLA-E- and HLA-A2-restricted Mycobacterium tuberculosis-specific CD8+ T cells were tested in vitro for cytotoxic and microbicidal activities, and their frequencies and phenotypes were evaluated ex vivo in patients with active tuberculosis and concomitant HIV-1 infection. HIV-1 and Mycobacterium tuberculosis coinfection caused downmodulation of HLA-A2 expression in human monocyte-derived macrophages associated with resistance to lysis by HLA-A2-restricted CD8+ T cells and failure to restrict the growth of intracellular Mycobacterium tuberculosis. Conversely, HLA-E surface expression and HLA-E-restricted cytolytic and microbicidal CD8 responses were not affected. HLA-E-restricted and Mycobacterium tuberculosis-specific CD8+ T cells were expanded in the circulation of patients with Mycobacterium tuberculosis/HIV-1 coinfection, as measured by tetramer staining, but displayed a terminally differentiated and exhausted phenotype that was rescued in vitro by anti-PD-1 (programmed cell death protein 1) monoclonal antibody. Together, these results indicate that HLA-E-restricted and Mycobacterium tuberculosis-specific CD8+ T cells in patients with Mycobacterium tuberculosis/HIV-1 coinfection have an exhausted phenotype and fail to expand in vitro in response to antigen stimulation, which can be restored by blocking the PD-1 pathway using the specific monoclonal antibody nivolumab.


我们研究了人类白细胞抗原 A2 (HLA-A2) 和 HLA-E 限制性 CD8 + T 细胞在结核分枝杆菌和人类免疫缺陷病病毒 HIV-1) 共感染患者中的作用。HIV-1 下调感染细胞中的 HLA-A 、-B 和-C 分子,因此,由于病毒无法下调其表达,影响 HLA I 类限制性 CD8 + T 细胞的识别,而不影响 HLA-E 限制性 CD8 + T 细胞的识别。因此,抗原特异性 HLA-E 限制性 CD8 + T 细胞可在结核分枝杆菌和 HIV-1 共感染中发挥保护作用。体外检测 HLA-E 和 HLA-A2-restricted 结核分枝杆菌特异性 CD8 + T 细胞的细胞毒性和杀微生物活性,并在活动性结核合并 HIV-1 感染患者中进行了体外频率和表型评估。HIV-1 和结核分枝杆菌共感染引起人单核细胞来源的巨噬细胞 HLA-A2 表达下调,与 HLA-A2-restricted CD8 + T 细胞裂解相关,未能限制细胞内结核分枝杆菌的生长。相反,HLA-E 表面表达和 HLA-E 限制性溶细胞和杀微生物 CD8 反应不受影响。通过四聚体染色测定,HLA-E 限制性和结核分枝杆菌特异性 CD8 + T 细胞在结核分枝杆菌/HIV-1 共感染患者的循环中扩增,但表现出终末分化和耗竭的表型,在体外被 anti-PD-1 (程序性细胞死亡蛋白 1) 单克隆抗体拯救。一起,这些结果表明,结核分枝杆菌/HIV-1 共感染患者的 HLA-E 限制性和结核分枝杆菌特异性 CD8 + T 细胞具有耗竭的表型,并且不能在体外响应抗原扩增。刺激,其可以通过使用特异性单克隆抗体 nivolumab 阻断 PD-1 通路来恢复。



作者列表:["Ria Goswami","Ashley N. Nelson","Joshua J. Tu","Maria Dennis","Liqi Feng","Amit Kumar","Jesse Mangold","Riley J. Mangan","Cameron Mattingly","Alan D. Curtis","Veronica Obregon-Perko","Maud Mavigner","Justin Pollara","George M. Shaw","Katharine J. Bar","Ann Chahroudi","Kristina De Paris","Cliburn Chan","Koen K. A. Van Rompay","Sallie R. Permar"]

METHODS:Novel interventions that do not rely on daily adherence to ART are needed to achieve sustained viral remission for perinatally infected children, who currently rely on lifelong ART. Considering the risks and expense associated with ART interruption trials, the identification of biomarkers of viral rebound will prioritize promising therapeutic intervention strategies, including anti-HIV Env protein therapeutics. However, comprehensive studies to identify those biomarkers are logistically challenging in human infants, demanding the need for relevant nonhuman primate models of HIV rebound. In this study, we developed an infant RM model of oral infection with simian-human immunodeficiency virus expressing clade C HIV Env and short-term ART followed by ATI, longitudinally characterizing the immune responses to viral infection during ART and after ATI. Additionally, we compared this infant RM model to an analogous adult RM rebound model and identified virologic and immunologic correlates of the time to viral rebound after ATI.To achieve long-term viral remission in human immunodeficiency virus (HIV)-infected children, novel strategies beyond early antiretroviral therapy (ART) will be necessary. Identifying clinical predictors of the time to viral rebound upon ART interruption will streamline the development of novel therapeutic strategies and accelerate their evaluation in clinical trials. However, identification of these biomarkers is logistically challenging in infants, due to sampling limitations and the potential risks of treatment interruption. To facilitate the identification of biomarkers predicting viral rebound, we have developed an infant rhesus macaque (RM) model of oral simian-human immunodeficiency virus (SHIV) SHIV.CH505.375H.dCT challenge and analytical treatment interruption (ATI) after short-term ART. We used this model to characterize SHIV replication kinetics and virus-specific immune responses during short-term ART or after ATI and demonstrated plasma viral rebound in 5 out of 6 (83%) infants. We observed a decline in humoral immune responses and partial dampening of systemic immune activation upon initiation of ART in these infants. Furthermore, we monitored SHIV replication and rebound kinetics in infant and adult RMs and found that both infants and adults demonstrated equally potent virus-specific humoral immune responses. Finally, we validated our models by confirming a well-established correlate of the time to viral rebound, namely, the pre-ART plasma viral load, as well as identified additional potential humoral immune correlates. Thus, this model of infant ART and viral rebound can be used and further optimized to define biomarkers of viral rebound following long-term ART as well as to preclinically assess novel therapies to achieve a pediatric HIV functional cure.

翻译标题与摘要 下载文献
作者列表:["E. R. Job","T. Ysenbaert","A. Smet","A. Van Hecke","L. Meuris","H. Kleanthous","X. Saelens","T. U. Vogel"]

METHODS:There is a pressing need for next-generation influenza vaccine strategies that are better able to manage antigenic drift and the cocirculation of multiple drift variants and that consistently improve vaccine effectiveness. Influenza virus NA is a key target antigen as a component of a next-generation vaccine in the influenza field, with evidence for a role in protective immunity in humans. However, mechanisms of protection provided by antibodies directed to NA remain largely unexplored. Herein, we show that antibody Fc interaction with Fcγ receptors (FcγRs) expressed on effector cells contributes to viral control in a murine model of influenza. Importantly, a chimeric mouse-human IgG1 with no direct antiviral activity was demonstrated to solely rely on FcγRs to protect mice from disease. Therefore, antibodies without NA enzymatic inhibitory activity may also play a role in controlling influenza viruses and should be of consideration when designing NA-based vaccines and assessing immunogenicity.Influenza virus neuraminidase (NA) has been under intense study recently as a vaccine antigen, yet there remain unanswered questions regarding the immune response directed toward NA. Antibodies (Abs) that can inhibit NA activity have been shown to aid in the control of disease caused by influenza virus infection in humans and animal models, yet how and if interactions between the Fc portion of anti-NA Abs and Fcγ receptors (FcγR) contribute to protection has not yet been extensively studied. Herein, we show that poly- and monoclonal anti-NA IgG antibodies with NA inhibitory activity can control A(H1N1)pdm09 infection in the absence of FcγRs, but FcγR interaction aided in viral clearance from the lungs. In contrast, a mouse-human chimeric anti-NA IgG1 that was incapable of mediating NA inhibition (NI) solely relied on FcγR interaction to protect transgenic mice (with a humanized FcγR compartment) against A(H1N1)pdm09 infection. As such, this study suggests that NA-specific antibodies contribute to protection against influenza A virus infection even in the absence of NI activity and supports protection through multiple effector mechanisms.

翻译标题与摘要 下载文献
作者列表:["Tiziana Lazzarotto","Daniel Blázquez-Gamero","Marie-Luce Delforge","Ina Foulon","Suzanne Luck","Suzanne Luck","Susanne Modrow","Marianne Leruez-Ville"]

METHODS:Maternal primary and non-primary cytomegalovirus (CMV) infection during pregnancy can result in in utero transmission to the developing fetus. Congenital CMV (cCMV) can result in significant morbidity, mortality or long-term sequelae, including sensorineural hearing loss, the most common sequela. As a leading cause of congenital infections worldwide, cCMV infection meets many of the criteria for screening. However, currently there are no universal programs that offer maternal or neonatal screening to identify infected mothers and infants, no vaccines to prevent infection, and no efficacious and safe therapies available for the treatment of maternal or fetal CMV infection. Data has shown that there are several maternal and neonatal screening strategies, and diagnostic methodologies, that allow the identification of those at risk of developing sequelae and adequately detect cCMV. Nevertheless, many questions remain unanswered in this field. Well-designed clinical trials to address several facets of CMV treatment (in pregnant women, CMV-infected fetuses and both symptomatic and asymptomatic neonates and children) are required. Prevention (vaccines), biology and transmission factors associated with non-primary CMV, and the cost-effectiveness of universal screening, all demand further exploration to fully realize the ultimate goal of preventing cCMV. In the meantime, prevention of primary infection during pregnancy should be championed to all by means of hygiene education.