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Human immunodeficiency virus type 1 (HIV-1) infection causes considerable morbidity and mortality worldwide. Although antiretroviral therapy (ART) has largely transformed HIV infection from a fatal disease to a chronic condition, approximately 10%-40% of HIV-infected individuals who receive effective ART and sustain long-term viral suppression still cannot achieve optimal immune reconstitution. These patients are called immunological nonresponders, a state associated with poor clinical prognosis. Mucosal-associated invariant T (MAIT) cells are an evolutionarily conserved unconventional T-cell subset defined by expression of semi-invariant αβ T-cell receptor (TCR), which recognizes metabolites derived from the riboflavin biosynthetic pathway presented on major histocompatibility complex-related protein-1. MAIT cells, which are considered to act as a bridge between innate and adaptive immunity, produce a wide range of cytokines and cytotoxic molecules upon activation through TCR-dependent and TCR-independent mechanisms, which is of major importance in defense against a variety of pathogens. In addition, MAIT cells are involved in autoimmune and immune-mediated diseases. The number of MAIT cells is dramatically and irreversibly decreased in the early stage of HIV infection and is not fully restored even after long-term suppressive ART. In light of the important role of MAIT cells in mucosal immunity and because microbial translocation is inversely associated with CD4

Antiretroviral therapy (ART) is the most generally used to treat human immunodeficiency virus (HIV)-infected patients. However, some patients experience incomplete immune reconstitution and fail to restore CD4+ T cell counts after treating with ART. Herein, we investigated the characters of CD4+CD8+ double-positive (DP) T cells at the transcriptomic level by analyzing single-cell RNA sequencing of peripheral blood mononuclear cells from HIV-infected immunological non-responders (INRs) and immunological responders (IRs). We identified eight DP T cell clusters and grouped into three populations CD4highCD8low, CD4lowCD8high, and CD4lowCD8low, respectively. Decreased proportion of DP T cells was detected in INRs, including CD4highCD8low DP T cells in the process of cellular differentiation, the latter demonstrated a reduced source of DP T cells in INRs. CD4highCD8low DP T cells in IRs and INRs as a heterogenous population, were distinct on the expression of GZMA/B/H, LAG3, NKG7 and GNLY, which related to the function of cell activation and cellular differentiation, cytotoxicity and programmed cell death. These data provide a comprehensive analysis of gene signatures of CD4highCD8low DP T cells associated with failed immune reconstitution after HIV infection, which could be useful in developing new cure strategies for HIV-infected patients.

Jie Jia,1,2 Ji-Qun Yang,3 Ying-Rong Du,3 Yu Xu,2 Deshenyue Kong,1,2 Xiu-Ling Zhang,3 Jun-Hong Mao,1,2 Gui-Fang Hu,3 Kun-Hua Wang,1,2,4 Yi-Qun Kuang1,2 1NHC Key Laboratory of Drug Addiction Medicine, First Affiliated Hospital of Kunming Medical University, Kunming Medical University, Kunming, 650032, People’s Republic of China; 2Scientific Research Laboratory Center, First Affiliated Hospital of Kunming Medical University, Kunming, 650032, People’s Republic of China; 3Third People’s Hospital of Kunming City/Drug Rehabilitation Hospital of Kunming City, Kunming, 650041, People’s Republic of China; 4School of Medicine, Yunnan University, Kunming, 650500, People’s Republic of ChinaCorrespondence: Yi-Qun Kuang; Kun-Hua Wang, NHC Key Laboratory of Drug Addiction Medicine, First Affiliated Hospital of Kunming Medical University, Kunming Medical University, Kunming, 650032, People’s Republic of China, Email yq610433@hotmail.com; wangkunhua1964@126.comBackground: Hypertension is a common complication in injection drug users (IDU), especially a high proportion of resistant hypertension occurs among them. However, the involving mechanisms remain largely unknown.Methods: We here investigated the key signaling moieties in resistant hypertension in drug users. Analyses were performed with high-throughput transcriptomic sequencing data of peripheral blood from individuals with drug-sensitive hypertension (Ctrl-DS), IDU with resistant hypertension (IDU-DR), and IDU with sensitive hypertension (IDU-DS).Results: We showed that 17 and 1 genes in IDU-DS, 48 and 4 genes in IDU-DR were upregulated and downregulated compared Ctrl-DS, and 2 and 4 genes were upregulated and downregulated in IDU-DR compared with IDU-DS, respectively (p ≤ 0.01 and |log2(FC)| ≥ 1). Differentially expressed genes (DEGs) between Ctrl-DS and IDU-DS were mainly involved in Gene ontology terms of immunoglobulin complex and blood microparticle. DEGs between IDU-DS and IDU-DR were mainly involved in immune system process and immunoglobulin complex. DEGs between Ctrl-DS and IDU-DR were mainly involved in immunoglobulin complex, blood microparticle and cytoplasmic vesicle lumen. We identified 2 gene clusters (brown modules, MEbrown; turquoise module, MEturquoise) correlated with IDU-DR and a gene cluster (magenta module, MEmagenta) correlated with IDU-DS by weighted gene co-expression network analysis (WGCNA). Functional analysis demonstrated that pathways of focal adhesion and focalin-1-rich granule lumen were involved in the development of IDU-DR, and the cytosolic large ribosomal subunit may relate to IDU-DR. Further, immune cell infiltration analysis demonstrated that the abundance of dendritic cells (DCs), natural Treg cells (nTreg), and exhausted T cells (Tex) in IDU-DR and IDU-DS, naïve CD8+ T cells in IDU-DS was significantly different compared with that in Ctrl-DS. The abundance of cytotoxic T cells (Tc) was significantly different between IDU-DS and IDU-DR.Conclusion: Our findings indicated a potential function of immunoregulation mechanisms for resistant hypertension.Keywords: drug use, hypertension, treatment-resistant, transcriptome, immunoregulation

Drug withdrawal elicits immune responses that contribute to the development of withdrawal symptoms and relapse. The understanding of the immunologic dynamics after drug withdrawal is limited, precluding the finding of promising immune intervention measures. Here, we performed cytokine and multiplex immune profiling in heroin, methamphetamine (METH) and ephedrine users after withdrawal and identified the correlation between cytokines and other immune parameters. We showed that broad and strong inflammatory responses occurred at the early stage after drug withdrawal, and the inflammatory responses showed a downtrend with the extension of withdrawal time. Notably, immune dysregulation remained through and may last longer than 12 months after withdrawal in heroin and METH users. Our findings suggest that cytokines, immune cells, complement and immunoglobulin form a complex immune network that regulates immune responses after withdrawal. These data provide a reference for future scientific research and drug research and development.

Methamphetamine (METH) is an illegal drug widely abused in many countries. Methamphetamine abuse is a major health and social problem all over the world. However, the effects of METH on the digestive system have rarely been reported. Previous studies and clinical cases have shown that METH use can lead to the impaired intestinal barrier function and severe digestive diseases. METH can cause multiple organ dysfunction, especially in the central nervous system (CNS). The gut microbiota are involved in the development of various CNS-related diseases

Methamphetamine (METH) is a highly addictive, psychoactive drug which can harm individual health and lead to great social problems. Various approaches have been adopted to address the problems arising from METH addiction, but relapse rates remain high. Recently, it has been found that comprehensive treatment combined with scientific and appropriate exercise interventions can improve the mental state and physical fitness of drug addicts and promote their physical and mental rehabilitation. Long-term, regular exercise improves the symptoms of METH withdrawal and reduces METH relapse. This study aimed to investigate the effects and regulated gene expression related to running exercise in METH-addicted mice.Male C57BL/6J mice were used to construct a METH addiction model. We performed a running exercise intervention and used conditioned place preference (CPP) to measure the effects of the running intervention on the METH-addicted mice. We also performed RNA sequencing (RNA-seq) and transcriptome analysis on the mice hippocampi, and the functions and differentially expressed genes (DEGs) that were significantly regulated by exercise intervention in the METH-addicted mice were analyzed and noted.The results showed that days of CPP were shortened to 3 days in METH-addicted mice that underwent moderate exercise intervention, compared to 6 days in METH-addicted mice that went without exercise intervention. In addition, hippocampal transcriptome analysis revealed 12 DEGs significantly regulated by exercise intervention. By performing Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, it was revealed that the function of immune responses was significantly enriched in the METH-addicted mice undertaking exercise. The expression of 12 DEGs was verified by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR), which showed that relative messenger RNA (mRNA) expression of DEGs was consistent with the RNA-seq results.A running intervention can promote the recovery of METH addiction in mice, and the 12 candidate DEGs from the mouse hippocampus can be used for further research on the regulatory mechanisms of exercise in METH-addicted mice.

Background: Drug withdrawal elicits immune responses contributing to the development of withdrawal symptoms and relapse. The understanding of the immunologic dynamics after drug withdrawal is limited, precluding the finding of promising immune intervention measures. Methods: We performed cytokine and multiplex immune profiling in drug users after withdrawal and identified the correlation between 27 cytokines and other immune parameters. Findings: We showed that broad and strong inflammatory responses occurred at the early stage after drug withdrawal, and the inflammatory responses showed a downtrend with the extension of withdrawal time. Notably, immune dysregulation still exists and may last longer in heroin and METH users after withdrawal for 12 months. IL-7 may play an important role in regulating the immune responses after drug withdrawal. Moreover, after withdrawal within 15 days, the Th1 cytokine (IL-2) was decreased markedly, but the Th2 cytokines (IL-4, IL-6 and IL-10) increased significantly compared with healthy controls in heroin users. Interpretation: Our findings suggest the cytokines, immune cells, complement and immunoglobulin form a complex immune network in regulating immune responses after withdrawal, which indicates immunotherapy as a promising immune intervention measure for drug relapse. Funding: Funded by the National Natural Science Foundation of China (81660094, 32060177), the Fund for Yunling Scholar (YLXL20170002) and the General Joint Project of the Department of Science and Technology of Yunnan Province and Kunming Medical University (2017FE467(-038), 2017FE467(-130)) etc. Declaration of Interest: The authors declare no competing interests. Ethical Approval: All methods and recruitment procedures described were approved by the Research Ethics Committee of the First Affiliated Hospital of Kunming Medical University (No. 2018 Lunshen L42)