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Background: Populations of natural killer cells lacking CD56 expression [CD56neg natural killer (NK) cells] have been demonstrated to expand during human immunodeficiency virus (HIV)-1 infection. However, their phenotypic and functional characteristics have not been systematically analyzed, and their roles during disease progression remain poorly understood. Methods: In this study, 84 donors, namely 34 treatment-naïve HIV-1-infected patients (TNs), 29 HIV-1-infected patients with successful antiretroviral therapy (ARTs), and 21 healthy controls (HCs), were enrolled. The phenotypic and functional characteristics of CD56neg NK cells were analyzed using single-cell RNA-sequencing (scRNA-seq) and flow cytometry. A potential link between the characteristics of CD56neg NK cells and the clinical parameters associated with HIV-1 disease progression was examined. Results: The frequency of the CD56neg NK cell population was significantly increased in TNs, which could be partially rescued by ART. Flow cytometry analyses revealed that CD56neg NK cells were characterized by high expression of CD39, TIGIT, CD95, and Ki67 compared to CD56dim NK cells. In vitro assays revealed reduced IFN-γ and TNF-α secretion, as well as decreased expression of granzyme B and perforin in CD56neg NK cells. In line with the data obtained by flow cytometry, scRNA-seq analysis further demonstrated impaired cytotoxic activities of CD56neg NK cells. Notably, a negative correlation was observed between CD39, CD95, and Ki67 expression levels in CD56neg NK cells and CD4+ T cell counts. Conclusions: The results presented in this study indicate that the CD56neg NK cell population expanded in HIV-1-infected individuals is dysfunctional and closely correlates with HIV-1 disease progression. [ABSTRACT FROM AUTHOR]

Background: Targeting immune checkpoints for HIV treatment potentially provides a double benefit resulting from the ability to restore viral-specific CD8+ T-cell functions and enhance HIV production from reservoir cells. Despite promising pre-clinical data, PD-1 blockade alone in HIV-1-infected patients with advanced cancer has shown limited benefits in controlling HIV, suggesting the need for additional targets beyond PD-1. CD39 and PD-1 are highly co-expressed on CD8+ T cells in HIV-1 infection. However, the characteristics of CD39 and PD-1 dual-positive CD8+ T-cell subsets in chronic HIV-1 infection remain poorly understood. Methods: This study enrolled 72 HIV-1-infected patients, including 40 treatment naïve and 32 ART patients. A total of 11 healthy individuals were included as controls. Different subsets of CD8+ T cells defined by CD39 and/or PD-1 expression were studied by flow cytometry. The relationships between the frequencies of the different subsets and parameters indicating HIV-1 disease progression were analyzed. Functional (i.e., cytokine secretion, viral inhibition) assays were performed to evaluate the impact of the blockade of adenosine and/or PD-1 signaling on CD8+ T cells. Results: The proportions of PD-1+, CD39+, and PD-1+CD39+ CD8+ T cells were significantly increased in treatment naïve patients but were partially lowered in patients on antiretroviral therapy. In treatment naïve patients, the proportions of PD-1+CD39+ CD8+ T cells were negatively correlated with CD4+ T-cell counts and the CD4/CD8 ratio, and were positively correlated with viral load. CD39+CD8+ T cells expressed high levels of the A2A adenosine receptor and were more sensitive to 2-chloroadenosine-mediated functional inhibition than their CD39- counterparts. In vitro , a combination of blocking CD39/adenosine and PD-1 signaling showed a synergic effect in restoring CD8+ T-cell function, as evidenced by enhanced abilities to secrete functional cytokines and to kill autologous reservoir cells. Conclusion: In patients with chronic HIV-1 infection there are increased frequencies of PD-1+, CD39+, and PD-1+CD39+ CD8+ T cells. In treatment naïve patients, the frequencies of PD-1+CD39+ CD8+ T cells are negatively correlated with CD4+ T-cell counts and the CD4/CD8 ratio and positively correlated with viral load. Combined blockade of CD39/adenosine and PD-1 signaling in vitro may exert a synergistic effect in restoring CD8+ T-cell function in HIV-1-infected patients. [ABSTRACT FROM AUTHOR]

Research has shown that learners do not always engage in appropriate metacognitive and self-regulatory processes while learning complex historical topics. However, little research exists to guide the design of technology-rich learning environments as metacognitive tools in history education. In order to address this issue, we designed a metacognitive tool using a bottom-up approach. Thirty-two undergraduate students read an historical narrative text either with or without the benefit of the metacognitive tool. Results from process and product data suggest that learners using the metacognitive tool had better recall and that the tool helped them (a) notice that particular events in an historical narrative text are unexplained, and (b) generate hypothetical causes to explain the occurrence of such events. We discuss the implications of these findings for the development of the MetaHistoReasoning Tool, a technology-rich learning environment that assist learners in terms of regulating their learning while they accomplish authentic tasks of historical inquiry. [ABSTRACT FROM AUTHOR]

Recent studies highlighted that CD8+ T cells are necessary for restraining reservoir in HIV-1-infected individuals who undergo antiretroviral therapy (ART), whereas the underlying cellular and molecular mechanisms remain largely unknown. Here, we enrolled 60 virologically suppressed HIV-1-infected individuals, to assess the correlations of the effector molecules and phenotypic subsets of CD8+ T cells with HIV-1 DNA and cell-associated unspliced RNA (CA usRNA). We found that the levels of HIV-1 DNA and usRNA correlated positively with the percentage of CCL4+CCL5- CD8+ central memory cells (T CM ) while negatively with CCL4-CCL5+ CD8+ terminally differentiated effector memory cells (T EMRA ). Moreover, a virtual memory CD8+ T cell (T VM ) subset was enriched in CCL4-CCL5+ T EMRA cells and phenotypically distinctive from CCL4+ T CM subset, supported by single-cell RNA-Seq data. Specifically, T VM cells showed superior cytotoxicity potentially driven by T-bet and RUNX3, while CCL4+ T CM subset displayed a suppressive phenotype dominated by JUNB and CREM. In viral inhibition assays, T VM cells inhibited HIV-1 reactivation more effectively than non-T VM CD8+ T cells, which was dependent on CCL5 secretion. Our study highlights CCL5-secreting T VM cells subset as a potential determinant of HIV-1 reservoir size. This might be helpful to design CD8+ T cell-based therapeutic strategies for cure of the disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hu, Li, Zhen, Wang, Huang, Zou, Zheng, Huang, Meng, Jin, Li, Zhou, Fu, Zhang, Li, Yang, Wang, Yang, Song, Fan, Jiao, Xu, Zhang, Zhou, Yuan, Huang, Qin, Wu, Shi, Wang and Zhang.)

Background: Populations of natural killer cells lacking CD56 expression [CD56 neg natural killer (NK) cells] have been demonstrated to expand during human immunodeficiency virus (HIV)-1 infection. However, their phenotypic and functional characteristics have not been systematically analyzed, and their roles during disease progression remain poorly understood., Methods: In this study, 84 donors, namely 34 treatment-naïve HIV-1-infected patients (TNs), 29 HIV-1-infected patients with successful antiretroviral therapy (ARTs), and 21 healthy controls (HCs), were enrolled. The phenotypic and functional characteristics of CD56 neg NK cells were analyzed using single-cell RNA-sequencing (scRNA-seq) and flow cytometry. A potential link between the characteristics of CD56 neg NK cells and the clinical parameters associated with HIV-1 disease progression was examined., Results: The frequency of the CD56 neg NK cell population was significantly increased in TNs, which could be partially rescued by ART. Flow cytometry analyses revealed that CD56 neg NK cells were characterized by high expression of CD39, TIGIT, CD95, and Ki67 compared to CD56 dim NK cells. In vitro assays revealed reduced IFN-γ and TNF-α secretion, as well as decreased expression of granzyme B and perforin in CD56 neg NK cells. In line with the data obtained by flow cytometry, scRNA-seq analysis further demonstrated impaired cytotoxic activities of CD56 neg NK cells. Notably, a negative correlation was observed between CD39, CD95, and Ki67 expression levels in CD56 neg NK cells and CD4 + T cell counts., Conclusions: The results presented in this study indicate that the CD56 neg NK cell population expanded in HIV-1-infected individuals is dysfunctional and closely correlates with HIV-1 disease progression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Cao, Zhang, Wan, Li, Mu, Guo, Zhou, Shen, Zhang, Fan, Jiao, Xu, Zhou, Yuan, Wang, Wang and Song.)

Background: Targeting immune checkpoints for HIV treatment potentially provides a double benefit resulting from the ability to restore viral-specific CD8 + T-cell functions and enhance HIV production from reservoir cells. Despite promising pre-clinical data, PD-1 blockade alone in HIV-1-infected patients with advanced cancer has shown limited benefits in controlling HIV, suggesting the need for additional targets beyond PD-1. CD39 and PD-1 are highly co-expressed on CD8 + T cells in HIV-1 infection. However, the characteristics of CD39 and PD-1 dual-positive CD8 + T-cell subsets in chronic HIV-1 infection remain poorly understood., Methods: This study enrolled 72 HIV-1-infected patients, including 40 treatment naïve and 32 ART patients. A total of 11 healthy individuals were included as controls. Different subsets of CD8 + T cells defined by CD39 and/or PD-1 expression were studied by flow cytometry. The relationships between the frequencies of the different subsets and parameters indicating HIV-1 disease progression were analyzed. Functional (i.e., cytokine secretion, viral inhibition) assays were performed to evaluate the impact of the blockade of adenosine and/or PD-1 signaling on CD8 + T cells., Results: The proportions of PD-1 + , CD39 + , and PD-1 + CD39 + CD8 + T cells were significantly increased in treatment naïve patients but were partially lowered in patients on antiretroviral therapy. In treatment naïve patients, the proportions of PD-1 + CD39 + CD8 + T cells were negatively correlated with CD4 + T-cell counts and the CD4/CD8 ratio, and were positively correlated with viral load. CD39 + CD8 + T cells expressed high levels of the A2A adenosine receptor and were more sensitive to 2-chloroadenosine-mediated functional inhibition than their CD39 - counterparts. In vitro , a combination of blocking CD39/adenosine and PD-1 signaling showed a synergic effect in restoring CD8 + T-cell function, as evidenced by enhanced abilities to secrete functional cytokines and to kill autologous reservoir cells., Conclusion: In patients with chronic HIV-1 infection there are increased frequencies of PD-1 + , CD39 + , and PD-1 + CD39 + CD8 + T cells. In treatment naïve patients, the frequencies of PD-1 + CD39 + CD8 + T cells are negatively correlated with CD4 + T-cell counts and the CD4/CD8 ratio and positively correlated with viral load. Combined blockade of CD39/adenosine and PD-1 signaling in vitro may exert a synergistic effect in restoring CD8 + T-cell function in HIV-1-infected patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Li, Huang, Tu, Zhou, Hu, Fu, Li, Yang, Song, Fan, Jiao, Xu, Zhang, Zhou, Yuan, Zhen, Shi, Wang and Zhang.)