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Bhattarai S, Kadry R, Yeapuri P, Lu Y, Foster EG, Zhang C, Dash P, Poluektova LY, Gorantla S, Mosley RL, Gendelman HE. HIV-1 infection facilitates Alzheimer's disease pathology in humanized APP knock-in immunodeficient mice. NEUROIMMUNE PHARMACOLOGY AND THERAPEUTICS 2025; 4:27-38. [PMID: 40309515 PMCID: PMC12041850 DOI: 10.1515/nipt-2024-0018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Accepted: 11/18/2024] [Indexed: 05/02/2025]
Abstract
Objectives Amyloid-β (Aβ) plaque deposition in the brain is a principal pathological feature of both Alzheimer's disease (AD) and progressive human immunodeficiency virus type one (HIV-1) infection. Both enable Aβ assembly and Aβ protein aggregation. The potential link between HIV-1 and AD remains uncertain, supporting the need for a reliable animal model. HIV-1 is tropic and pathogenic for humans. It does not replicate in mice. The restricted species tropism has slowed progress in basic research activities. The current study seeks to correct animal model limitations. Methods We created an AD mouse to address the need to develop an small animal model that allows studies of viral infection by making a knock-in (KI) with the human amyloid precursor protein (APP)KM670,671NL Swedish mutation to the mouse genome. The resulting founder mice were crossed with immunodeficient NOG (NOD. Cg-Prkdc scid Il2rg tm1Sug Tg(CMV-IL-34)1/Jic) to generate NOG/APPKM670,671NL/IL-34 (NAIL) mice. The mice were reconstituted with human hematopoietic stem cells to generate NAIL mice with functional adaptive and innate human immune systems. Four-month-old, humanized NAIL mice were infected with HIV-1ADA, a macrophage-tropic viral strain then evaluated for viral infection and AD pathology. Results Productive HIV-1 infection was confirmed by plasma HIV-1 RNA levels in infected NAIL mice. The viral load increased by tenfold between day 10 and day 25 post-infection. By day 25, viral DNA confirmed the establishment of HIV-1 reservoirs in CD45+ cells from the immune tissues of infected NAIL mice. Additionally, p24 measurements in lymphoid and brain tissues of NAIL mice validated productive HIV-1 infection. Amyloid burden from infected NAIL mice was increased. Immunofluorescence staining revealed co-localization of Aβ fibrils and HLA-DR+ microglia in infected NAIL mice. Conclusions These results highlight the AD-HIV model's unique pathobiological and infectious features where the viral and immune responses can now be measured.
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Affiliation(s)
- Shaurav Bhattarai
- Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Science, Omaha, NE, USA
| | - Rana Kadry
- Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Science, Omaha, NE, USA
| | - Pravin Yeapuri
- Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Science, Omaha, NE, USA
| | - Yaman Lu
- Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Science, Omaha, NE, USA
| | - Emma G. Foster
- Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Science, Omaha, NE, USA
| | - Chen Zhang
- Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Science, Omaha, NE, USA
| | - Prasanta Dash
- Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Science, Omaha, NE, USA
| | - Larisa Y. Poluektova
- Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Science, Omaha, NE, USA
| | - Santhi Gorantla
- Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Science, Omaha, NE, USA
| | - R. Lee Mosley
- Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Science, Omaha, NE, USA
| | - Howard E. Gendelman
- Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Science, Omaha, NE, USA
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Frouard J, Telwatte S, Luo X, Elphick N, Thomas R, Arneson D, Roychoudhury P, Butte AJ, Wong JK, Hoh R, Deeks SG, Lee SA, Roan NR, Yukl S. HIV-SEQ REVEALS GLOBAL HOST GENE EXPRESSION DIFFERENCES BETWEEN HIV-TRANSCRIBING CELLS FROM VIREMIC AND SUPPRESSED PEOPLE WITH HIV. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.12.17.629023. [PMID: 39763963 PMCID: PMC11702770 DOI: 10.1101/2024.12.17.629023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/18/2025]
Abstract
"Active" reservoir cells transcribing HIV can perpetuate chronic inflammation in virally suppressed people with HIV (PWH) and likely contribute to viral rebound after antiretroviral therapy (ART) interruption, so they represent an important target for new therapies. These cells, however, are difficult to study using single-cell RNA-seq (scRNA-seq) due to their low frequency and low levels of HIV transcripts, which are usually not polyadenylated. Here, we developed "HIV-seq" to enable more efficient capture of HIV transcripts - including non-polyadenylated ones - for scRNA-seq analysis of cells from PWH. By spiking in a set of custom-designed capture sequences targeting conserved regions of the HIV genome during scRNA-seq, we increased our ability to find HIV RNA+ cells from PWH by up to 44%. Implementing HIV-seq in conjunction with surface phenotyping by CITE-seq on paired blood specimens from PWH before vs. after ART suppression, we found that HIV RNA+ cells were enriched among T effector memory (Tem) cells during both viremia and ART suppression, but exhibited a cytotoxic signature during viremia only. By contrast, HIV RNA+ cells from the ART-suppressed timepoints exhibited a distinct anti-inflammatory signature involving elevated TGF-β and diminished IFN signaling. Overall, these findings demonstrate that active reservoir cells exhibit transcriptional features distinct from HIV RNA+ cells during viremia, and underscore HIV-seq as a useful tool to better understand the mechanisms by which HIV-transcribing cells can persist during ART.
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Affiliation(s)
- Julie Frouard
- Gladstone Institutes, San Francisco, CA 94158, USA
- Department of Urology, University of California, San Francisco, CA 94158, USA
| | - Sushama Telwatte
- San Francisco Veterans Affairs (VA) Medical Center and University of California, San Francisco, CA, USA
- Department of Infectious Diseases, The University of Melbourne at the Peter Doherty Institute of Infection and Immunity, Melbourne, Australia
| | - Xiaoyu Luo
- Gladstone Institutes, San Francisco, CA 94158, USA
- Department of Urology, University of California, San Francisco, CA 94158, USA
| | | | | | - Douglas Arneson
- Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA, USA
| | - Pavitra Roychoudhury
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA; Viral and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - Atul J Butte
- Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA, USA
| | - Joseph K Wong
- San Francisco Veterans Affairs (VA) Medical Center and University of California, San Francisco, CA, USA
| | - Rebecca Hoh
- Division of HIV, Infectious Diseases and Global Medicine, University of California, San Francisco, USA
| | - Steven G Deeks
- Division of HIV, Infectious Diseases and Global Medicine, University of California, San Francisco, USA
| | - Sulggi A Lee
- Zuckerberg San Francisco General Hospital and the University of California, San Francisco, USA
| | - Nadia R Roan
- Gladstone Institutes, San Francisco, CA 94158, USA
- Department of Urology, University of California, San Francisco, CA 94158, USA
| | - Steven Yukl
- San Francisco Veterans Affairs (VA) Medical Center and University of California, San Francisco, CA, USA
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Du J, Luo H, Ye S, Zhang H, Zheng Z, Liu K. Unraveling IFI44L's biofunction in human disease. Front Oncol 2024; 14:1436576. [PMID: 39737399 PMCID: PMC11682996 DOI: 10.3389/fonc.2024.1436576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Accepted: 11/26/2024] [Indexed: 01/01/2025] Open
Abstract
Interferon-induced protein 44-like (IFI44L) is regarded as an immune-related gene and is a member of interferon-stimulated genes (ISGs). They participate in network transduction, and its own epigenetic modifications, apoptosis, cell-matrix formation, and many other pathways in tumors, autoimmune diseases, and viral infections. The current review provides a comprehensive overview of the onset and biological mechanisms of IFI44L and its potential clinical applications in malignant tumors and non-neoplastic diseases.
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4
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Guo R, Kong J, Tang P, Wang S, Sang L, Liu L, Guo R, Yan K, Qi M, Bian Z, Song Y, Jiang Z, Li Y. Unbiased Single-Cell Sequencing of Hematopoietic and Immune Cells from Aplastic Anemia Reveals the Contributors of Hematopoiesis Failure and Dysfunctional Immune Regulation. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2304539. [PMID: 38145351 PMCID: PMC10933602 DOI: 10.1002/advs.202304539] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 10/24/2023] [Indexed: 12/26/2023]
Abstract
Aplastic anemia (AA) is a bone marrow (BM) failure syndrome mediated by hyperactivated T-cells with heterogeneous pathogenic factors. The onset of BM failure cannot be accurately determined in humans; therefore, exact pathogenesis remains unclear. In this study, a cellular atlas and microenvironment interactions is established using unbiased single-cell RNA-seq, along with multi-omics analyses (mass cytometry, cytokine profiling, and oxidized fatty acid metabolomics). A new KIR+ CD8+ regulatory T cells (Treg) subset is identified in patients with AA that engages in immune homeostasis. Conventional CD4+ T-cells differentiate into highly differentiated T helper cells with type 2 cytokines (IL-4, IL-6, and IL-13), GM-SCF, and IL-1β. Immunosuppressive homeostasis is impaired by enhanced apoptosis of activated Treg cells. Pathological Vδ1 cells dominated the main fraction of γδ T-cells. The B/plasma, erythroid, and myeloid lineages also exhibit substantial pathological features. Interactions between TNFSF12-TNFRSF12A, TNF-TNFRSF1A, and granzyme-gasdermin are associated with the cell death of hematopoietic stem/progenitor (HSPCs), Treg, and early erythroid cells. Ferroptosis, a major driver of HSPCs destruction, is identified in patients with AA. Furthermore, a case of twins with AA is reported to enhance the persuasiveness of the analysis. These results collectively constitute the cellular atlas and microenvironment interactions in patients with AA and provide novel insights into the development of new therapeutic opportunities.
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Affiliation(s)
- Rongqun Guo
- Department of HematologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan450052China
- Academy of Medical ScienceHenan Medical College of Zhengzhou UniversityZhengzhouHenan450052China
| | - Jingjing Kong
- Department of HematologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan450052China
| | - Ping Tang
- Department of HematologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan450052China
| | - Shuya Wang
- Department of Blood TransfusionThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan450052China
| | - Lina Sang
- Department of HematologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan450052China
| | - Liu Liu
- Department of HematologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan450052China
| | - Rong Guo
- Department of HematologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan450052China
| | - Ketai Yan
- Department of HematologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan450052China
- Academy of Medical ScienceHenan Medical College of Zhengzhou UniversityZhengzhouHenan450052China
| | - Mochu Qi
- Department of HematologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan450052China
| | - Zhilei Bian
- Department of HematologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan450052China
| | - Yongping Song
- Department of HematologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan450052China
| | - Zhongxing Jiang
- Department of HematologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan450052China
| | - Yingmei Li
- Department of HematologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan450052China
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5
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Chen X, Liao B, Ren T, Liao Z, Huang Z, Lin Y, Zhong S, Li J, Wen S, Li Y, Lin X, Du X, Yang Y, Guo J, Zhu X, Lin H, Liu R, Wang J. Adjuvant activity of cordycepin, a natural derivative of adenosine from Cordyceps militaris, on an inactivated rabies vaccine in an animal model. Heliyon 2024; 10:e24612. [PMID: 38293396 PMCID: PMC10826310 DOI: 10.1016/j.heliyon.2024.e24612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 01/10/2024] [Accepted: 01/11/2024] [Indexed: 02/01/2024] Open
Abstract
Vaccination is the most feasible way of preventing rabies, an ancient zoonosis that remains a major public health concern globally. However, administration of inactivated rabies vaccination without adjuvants is always inefficient and necessitates four to five injections. In the current study, we explored the adjuvant characteristics of cordycepin, a major bioactive component of Cordyceps militaris, to boost immune responses against a commercially available rabies vaccine. We found that cordycepin could stimulate stronger phenotypic and functional maturation of dendritic cells (DCs). For animal experiments, mice were immunized 3 times with rabies vaccine in the presence or absence of cordycepin at 1-week interval. Analysis of T cell differentiation and serum antibody isotypes showed that humoral immunity was dominant with a Th2 biased immune response. These results were also supported by the raised ratio of follicular helper T cells (TFH) and germinal center B cells (GCB). Thus, titer of rabies virus neutralizing antibody (RVNAb) and rabies virus-specific memory B cells were both raised as a result. Furthermore, administration of cordycepin did not cause pathological phenomena or body weight loss. The findings indicate that cordycepin could be used as a promising adjuvant for rabies vaccines to get a higher range of protection without any side effects.
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Affiliation(s)
- Xin Chen
- College of Pharmacy, Shenzhen Technology University, Shenzhen, 518118, China
- School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen, 518118, China
| | - Boyu Liao
- College of Pharmacy, Shenzhen Technology University, Shenzhen, 518118, China
- School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen, 518118, China
| | - Tianci Ren
- College of Pharmacy, Shenzhen Technology University, Shenzhen, 518118, China
| | - Zhipeng Liao
- College of Pharmacy, Shenzhen Technology University, Shenzhen, 518118, China
| | - Zijie Huang
- College of Pharmacy, Shenzhen Technology University, Shenzhen, 518118, China
| | - Yujuan Lin
- College of Pharmacy, Shenzhen Technology University, Shenzhen, 518118, China
| | - Shouhao Zhong
- College of Pharmacy, Shenzhen Technology University, Shenzhen, 518118, China
| | - Jiaying Li
- College of Pharmacy, Shenzhen Technology University, Shenzhen, 518118, China
| | - Shun Wen
- College of Pharmacy, Shenzhen Technology University, Shenzhen, 518118, China
| | - Yingyan Li
- College of Pharmacy, Shenzhen Technology University, Shenzhen, 518118, China
| | - Xiaohan Lin
- College of Pharmacy, Shenzhen Technology University, Shenzhen, 518118, China
| | - Xingchen Du
- College of Pharmacy, Shenzhen Technology University, Shenzhen, 518118, China
| | - Yuhui Yang
- College of Pharmacy, Shenzhen Technology University, Shenzhen, 518118, China
- School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen, 518118, China
| | - Jiubiao Guo
- College of Pharmacy, Shenzhen Technology University, Shenzhen, 518118, China
| | - Xiaohui Zhu
- College of Pharmacy, Shenzhen Technology University, Shenzhen, 518118, China
| | - Haishu Lin
- College of Pharmacy, Shenzhen Technology University, Shenzhen, 518118, China
- School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen, 518118, China
| | - Rui Liu
- Laboratory of Molecular Immunology, State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, 200438, China
| | - Jingbo Wang
- College of Pharmacy, Shenzhen Technology University, Shenzhen, 518118, China
- School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen, 518118, China
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6
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Zhang W, Li Y, Xin S, Yang L, Jiang M, Xin Y, Wang Y, Cao P, Zhang S, Yang Y, Lu J. The emerging roles of IFIT3 in antiviral innate immunity and cellular biology. J Med Virol 2023; 95:e28259. [PMID: 36305096 DOI: 10.1002/jmv.28259] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 08/23/2022] [Accepted: 10/25/2022] [Indexed: 01/11/2023]
Abstract
The interferon-inducible protein with tetrapeptide repeats 3 (IFIT3) is one of the most important members in both the IFIT family and interferon-stimulated genes family. IFIT3 has typical features of the IFIT family in terms of gene and protein structures, and is able to be activated through the classical PRRs-IFN-JAK/STAT pathway. A variety of viruses can induce the expression of IFIT3, which in turn inhibits the replication of viruses, with the underlying mechanism showing its crucial role in antiviral innate immunity. Emerging studies have also identified that IFIT3 is involved in cellular biology changes, including cell proliferation, apoptosis, differentiation, and cancer development. In this review, we summarize the characteristics of IFIT3 with respect to molecular structure and regulatory pathways, highlighting the role of IFIT3 in antiviral innate immunity, as well as its diverse biological roles. We also discuss the potential of IFIT3 as a biomarker in disease diagnosis and therapy.
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Affiliation(s)
- Wentao Zhang
- Hunan Cancer Hospital/the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Hunan, Changsha, China.,Department of Microbiology, School of Basic Medical Science, Central South University, Hunan, Changsha, China.,NHC Key Laboratory of Carcinogenesis, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Hunan, Changsha, China.,Department of Hematology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Hunan, Changsha, China.,China-Africa Research Center of Infectious Diseases, Central South University, Hunan, Changsha, China
| | - Yanling Li
- Hunan Cancer Hospital/the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Hunan, Changsha, China.,Department of Microbiology, School of Basic Medical Science, Central South University, Hunan, Changsha, China.,NHC Key Laboratory of Carcinogenesis, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Hunan, Changsha, China.,Department of Hematology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Hunan, Changsha, China.,China-Africa Research Center of Infectious Diseases, Central South University, Hunan, Changsha, China
| | - Shuyu Xin
- Hunan Cancer Hospital/the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Hunan, Changsha, China.,Department of Microbiology, School of Basic Medical Science, Central South University, Hunan, Changsha, China.,NHC Key Laboratory of Carcinogenesis, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Hunan, Changsha, China.,Department of Hematology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Hunan, Changsha, China.,China-Africa Research Center of Infectious Diseases, Central South University, Hunan, Changsha, China
| | - Li Yang
- Hunan Cancer Hospital/the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Hunan, Changsha, China.,Department of Microbiology, School of Basic Medical Science, Central South University, Hunan, Changsha, China.,NHC Key Laboratory of Carcinogenesis, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Hunan, Changsha, China.,Department of Hematology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Hunan, Changsha, China.,China-Africa Research Center of Infectious Diseases, Central South University, Hunan, Changsha, China
| | - Mingjuan Jiang
- Hunan Cancer Hospital/the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Hunan, Changsha, China.,Department of Microbiology, School of Basic Medical Science, Central South University, Hunan, Changsha, China.,NHC Key Laboratory of Carcinogenesis, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Hunan, Changsha, China.,Department of Hematology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Hunan, Changsha, China.,China-Africa Research Center of Infectious Diseases, Central South University, Hunan, Changsha, China
| | - Yujie Xin
- Hunan Cancer Hospital/the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Hunan, Changsha, China.,Department of Microbiology, School of Basic Medical Science, Central South University, Hunan, Changsha, China.,NHC Key Laboratory of Carcinogenesis, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Hunan, Changsha, China.,Department of Hematology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Hunan, Changsha, China.,China-Africa Research Center of Infectious Diseases, Central South University, Hunan, Changsha, China
| | - Yiwei Wang
- Hunan Cancer Hospital/the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Hunan, Changsha, China.,Department of Microbiology, School of Basic Medical Science, Central South University, Hunan, Changsha, China.,NHC Key Laboratory of Carcinogenesis, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Hunan, Changsha, China.,Department of Hematology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Hunan, Changsha, China.,China-Africa Research Center of Infectious Diseases, Central South University, Hunan, Changsha, China
| | - Pengfei Cao
- NHC Key Laboratory of Carcinogenesis, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Hunan, Changsha, China.,Department of Hematology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Hunan, Changsha, China
| | - Senmiao Zhang
- Hunan Cancer Hospital/the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Hunan, Changsha, China.,Department of Microbiology, School of Basic Medical Science, Central South University, Hunan, Changsha, China.,NHC Key Laboratory of Carcinogenesis, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Hunan, Changsha, China.,Department of Hematology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Hunan, Changsha, China.,China-Africa Research Center of Infectious Diseases, Central South University, Hunan, Changsha, China
| | - Yang Yang
- Hunan Cancer Hospital/the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Hunan, Changsha, China.,Department of Microbiology, School of Basic Medical Science, Central South University, Hunan, Changsha, China.,NHC Key Laboratory of Carcinogenesis, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Hunan, Changsha, China.,Department of Hematology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Hunan, Changsha, China.,China-Africa Research Center of Infectious Diseases, Central South University, Hunan, Changsha, China
| | - Jianhong Lu
- Hunan Cancer Hospital/the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Hunan, Changsha, China.,Department of Microbiology, School of Basic Medical Science, Central South University, Hunan, Changsha, China.,NHC Key Laboratory of Carcinogenesis, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Hunan, Changsha, China.,Department of Hematology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Hunan, Changsha, China.,China-Africa Research Center of Infectious Diseases, Central South University, Hunan, Changsha, China
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7
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Sertznig H, Roesmann F, Wilhelm A, Heininger D, Bleekmann B, Elsner C, Santiago M, Schuhenn J, Karakoese Z, Benatzy Y, Snodgrass R, Esser S, Sutter K, Dittmer U, Widera M. SRSF1 acts as an IFN-I-regulated cellular dependency factor decisively affecting HIV-1 post-integration steps. Front Immunol 2022; 13:935800. [PMID: 36458014 PMCID: PMC9706209 DOI: 10.3389/fimmu.2022.935800] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Accepted: 10/19/2022] [Indexed: 08/24/2023] Open
Abstract
Efficient HIV-1 replication depends on balanced levels of host cell components including cellular splicing factors as the family of serine/arginine-rich splicing factors (SRSF, 1-10). Type I interferons (IFN-I) play a crucial role in the innate immunity against HIV-1 by inducing the expression of IFN-stimulated genes (ISGs) including potent host restriction factors. The less well known IFN-repressed genes (IRepGs) might additionally affect viral replication by downregulating host dependency factors that are essential for the viral life cycle; however, so far, the knowledge about IRepGs involved in HIV-1 infection is very limited. In this work, we could demonstrate that HIV-1 infection and the associated ISG induction correlated with low SRSF1 levels in intestinal lamina propria mononuclear cells (LPMCs) and peripheral blood mononuclear cells (PBMCs) during acute and chronic HIV-1 infection. In HIV-1-susceptible cell lines as well as primary monocyte-derived macrophages (MDMs), expression levels of SRSF1 were transiently repressed upon treatment with specific IFNα subtypes in vitro. Mechanically, 4sU labeling of newly transcribed mRNAs revealed that IFN-mediated SRSF1 repression is regulated on early RNA level. SRSF1 knockdown led to an increase in total viral RNA levels, but the relative proportion of the HIV-1 viral infectivity factor (Vif) coding transcripts, which is essential to counteract APOBEC3G-mediated host restriction, was significantly reduced. In the presence of high APOBEC3G levels, however, increased LTR activity upon SRSF1 knockdown facilitated the overall replication, despite decreased vif mRNA levels. In contrast, SRSF1 overexpression significantly impaired HIV-1 post-integration steps including LTR transcription, alternative splice site usage, and virus particle production. Since balanced SRSF1 levels are crucial for efficient viral replication, our data highlight the so far undescribed role of SRSF1 acting as an IFN-modulated cellular dependency factor decisively regulating HIV-1 post-integration steps.
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Affiliation(s)
- Helene Sertznig
- Institute for Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Fabian Roesmann
- Institute for Medical Virology, University Hospital Frankfurt, Goethe University Frankfurt am Main, Frankfurt am Main, Germany
| | - Alexander Wilhelm
- Institute for Medical Virology, University Hospital Frankfurt, Goethe University Frankfurt am Main, Frankfurt am Main, Germany
| | - Delia Heininger
- Institute for Medical Virology, University Hospital Frankfurt, Goethe University Frankfurt am Main, Frankfurt am Main, Germany
| | - Barbara Bleekmann
- Institute for Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Carina Elsner
- Institute for Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Mario Santiago
- Department of Medicine, University of Colorado Denver, Aurora, CO, United States
| | - Jonas Schuhenn
- Institute for Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Zehra Karakoese
- Institute for Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Yvonne Benatzy
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt am Main, Frankfurt, Germany
| | - Ryan Snodgrass
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt am Main, Frankfurt, Germany
| | - Stefan Esser
- Clinic of Dermatology, University Hospital, University of Duisburg-Essen, Essen, Germany
| | - Kathrin Sutter
- Institute for Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Ulf Dittmer
- Institute for Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Marek Widera
- Institute for Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
- Institute for Medical Virology, University Hospital Frankfurt, Goethe University Frankfurt am Main, Frankfurt am Main, Germany
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8
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Sato H, Murakami T, Matsuura R, Abe M, Matsuoka S, Yashiroda Y, Yoshida M, Akari H, Nagasawa Y, Takei M, Aida Y. A Novel Class of HIV-1 Inhibitors Targeting the Vpr-Induced G2-Arrest in Macrophages by New Yeast- and Cell-Based High-Throughput Screening. Viruses 2022; 14:v14061321. [PMID: 35746791 PMCID: PMC9227106 DOI: 10.3390/v14061321] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2022] [Revised: 06/13/2022] [Accepted: 06/14/2022] [Indexed: 02/04/2023] Open
Abstract
The human immunodeficiency virus type 1 (HIV-1) accessory protein, Vpr, arrests the cell cycle of the G2 phase, and this Vpr-mediated G2 arrest is implicated in an efficient HIV-1 spread in monocyte-derived macrophages. Here, we screened new candidates for Vpr-targeting HIV-1 inhibitors by using fission yeast- and mammalian cell-based high-throughput screening. First, fission yeast strains expressing the HIV-1 Vpr protein were generated and then treated for 48 h with 20 μM of a synthetic library, including 140,000 chemical compounds. We identified 268 compounds that recovered the growth of Vpr-overexpressing yeast. The selected compounds were then tested in mammalian cells, and those displaying high cytotoxicity were excluded from further cell cycle analysis and imaging-based screening. A flow cytometry analysis confirmed that seven compounds recovered from the Vpr-induced G2 arrest. The cell toxicity and inhibitory effect of HIV-1 replication in human monocyte-derived macrophages (MDM) were examined, and three independent structural compounds, VTD227, VTD232, and VTD263, were able to inhibit HIV-1 replication in MDM. Furthermore, we showed that VTD227, but not VTD232 and VTD263, can directly bind to Vpr. Our results indicate that three new compounds and their derivatives represent new drugs targeting HIV-1 replication and can be potentially used in clinics to improve the current antiretroviral therapy.
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Affiliation(s)
- Hirotaka Sato
- Viral Infectious Diseases Unit, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan; (H.S.); (T.M.); (R.M.)
- Division of Hematology and Rheumatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-kamichou, Itabashi-ku, Tokyo 173-8610, Japan; (Y.N.); (M.T.)
- Department of Microbiology, Dokkyo Medical University School of Medicine, 880 Kitakobayashi, Mibu, Shimotsuga, Tochigi 321-0293, Japan
| | - Tomoyuki Murakami
- Viral Infectious Diseases Unit, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan; (H.S.); (T.M.); (R.M.)
- Division of Hematology and Rheumatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-kamichou, Itabashi-ku, Tokyo 173-8610, Japan; (Y.N.); (M.T.)
| | - Ryosuke Matsuura
- Viral Infectious Diseases Unit, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan; (H.S.); (T.M.); (R.M.)
- Division of Hematology and Rheumatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-kamichou, Itabashi-ku, Tokyo 173-8610, Japan; (Y.N.); (M.T.)
- Laboratory of Global Infectious Diseases Control Science, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
| | - Masako Abe
- Drug Discovery Seed Compounds Exploratory Unit, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan; (M.A.); (S.M.); (M.Y.)
| | - Seiji Matsuoka
- Drug Discovery Seed Compounds Exploratory Unit, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan; (M.A.); (S.M.); (M.Y.)
| | - Yoko Yashiroda
- Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan;
| | - Minoru Yoshida
- Drug Discovery Seed Compounds Exploratory Unit, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan; (M.A.); (S.M.); (M.Y.)
- Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan;
| | - Hirofumi Akari
- Center for the Evolutionary Origins of Human Behavior, Kyoto University, 41-2 Kanrin, Inuyama, Aichi 484-8506, Japan;
| | - Yosuke Nagasawa
- Division of Hematology and Rheumatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-kamichou, Itabashi-ku, Tokyo 173-8610, Japan; (Y.N.); (M.T.)
| | - Masami Takei
- Division of Hematology and Rheumatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-kamichou, Itabashi-ku, Tokyo 173-8610, Japan; (Y.N.); (M.T.)
| | - Yoko Aida
- Viral Infectious Diseases Unit, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan; (H.S.); (T.M.); (R.M.)
- Division of Hematology and Rheumatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-kamichou, Itabashi-ku, Tokyo 173-8610, Japan; (Y.N.); (M.T.)
- Laboratory of Global Infectious Diseases Control Science, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
- Correspondence:
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9
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Rao S, Mahmoudi T. DEAD-ly Affairs: The Roles of DEAD-Box Proteins on HIV-1 Viral RNA Metabolism. Front Cell Dev Biol 2022; 10:917599. [PMID: 35769258 PMCID: PMC9234453 DOI: 10.3389/fcell.2022.917599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Accepted: 05/23/2022] [Indexed: 11/13/2022] Open
Abstract
In order to ensure viral gene expression, Human Immunodeficiency virus type-1 (HIV-1) recruits numerous host proteins that promote optimal RNA metabolism of the HIV-1 viral RNAs (vRNAs), such as the proteins of the DEAD-box family. The DEAD-box family of RNA helicases regulates multiple steps of RNA metabolism and processing, including transcription, splicing, nucleocytoplasmic export, trafficking, translation and turnover, mediated by their ATP-dependent RNA unwinding ability. In this review, we provide an overview of the functions and role of all DEAD-box family protein members thus far described to influence various aspects of HIV-1 vRNA metabolism. We describe the molecular mechanisms by which HIV-1 hijacks these host proteins to promote its gene expression and we discuss the implications of these interactions during viral infection, their possible roles in the maintenance of viral latency and in inducing cell death. We also speculate on the emerging potential of pharmacological inhibitors of DEAD-box proteins as novel therapeutics to control the HIV-1 pandemic.
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Affiliation(s)
- Shringar Rao
- Department of Biochemistry, Erasmus University Medical Centre, Rotterdam, Netherlands
| | - Tokameh Mahmoudi
- Department of Biochemistry, Erasmus University Medical Centre, Rotterdam, Netherlands
- Department of Pathology, Erasmus University Medical Centre, Rotterdam, Netherlands
- Department of Urology, Erasmus University Medical Centre, Rotterdam, Netherlands
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10
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Deymier S, Louvat C, Fiorini F, Cimarelli A. ISG20: an enigmatic antiviral RNase targeting multiple viruses. FEBS Open Bio 2022; 12:1096-1111. [PMID: 35174977 PMCID: PMC9157404 DOI: 10.1002/2211-5463.13382] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 01/31/2022] [Accepted: 02/15/2022] [Indexed: 11/25/2022] Open
Abstract
Interferon-stimulated gene 20 kDa protein (ISG20) is a relatively understudied antiviral protein capable of inhibiting a broad spectrum of viruses. ISG20 exhibits strong RNase properties, and it belongs to the large family of DEDD exonucleases, present in both prokaryotes and eukaryotes. ISG20 was initially characterized as having strong RNase activity in vitro, suggesting that its inhibitory effects are mediated via direct degradation of viral RNAs. This mechanism of action has since been further elucidated and additional antiviral activities of ISG20 highlighted, including direct degradation of deaminated viral DNA and translational inhibition of viral RNA and nonself RNAs. This review focuses on the current understanding of the main molecular mechanisms of viral inhibition by ISG20 and discusses the latest developments on the features that govern specificity or resistance to its action.
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Affiliation(s)
- Séverine Deymier
- Centre International de Recherche en Infectiologie (CIRI)Université de LyonInsermU1111Université Claude Bernard Lyon 1CNRSUMR5308École Nationale Supérieur de LyonFrance
| | | | | | - Andrea Cimarelli
- Centre International de Recherche en Infectiologie (CIRI)Université de LyonInsermU1111Université Claude Bernard Lyon 1CNRSUMR5308École Nationale Supérieur de LyonFrance
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11
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Liu X, Lin L, Lu L, Li X, Han Y, Qiu Z, Li X, Li Y, Song X, Cao W, Li T. Comparative Transcriptional Analysis Identified Characteristic Genes and Patterns in HIV-Infected Immunological Non-Responders. Front Immunol 2022; 13:807890. [PMID: 35154126 PMCID: PMC8832504 DOI: 10.3389/fimmu.2022.807890] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 01/04/2022] [Indexed: 12/12/2022] Open
Abstract
Purpose The incomplete immune reconstitution is a complex phenomenon among human immunodeficiency virus (HIV)-infected patients despite the fact that they have achieved persistent viral suppression under the combined antiretroviral therapy. This study aims to screen and verify the immunological characteristics and underlying mechanisms of immunological non-responders (INRs). Methods The RNA-seq and the differentially expressed genes (DEGs) analysis were used to explore potential characteristics among INRs. Gene Ontology (GO) enrichment, ingenuity pathway analysis (IPA) analysis, Gene set enrichment analysis (GSEA) analysis, and the weighted gene co-expression network analysis (WGCNA) were used to explore the potential mechanism. The transcriptional meta-analysis was used to analyze the external efficiency. Results The RNA-seq identified 316 DEGs among INRs. The interferon signaling pathway was enriched via GO and IPA analysis among DEGs. The combined GSEA and WGCNA analysis confirmed that the IFN response was more correlated with INR. Furthermore, IFI27 (IFN-α Inducible Protein 27, also known as ISG12) was chosen based on combined DEG analysis, WGCNA analysis, and the transcriptional meta-analysis conducted on other published datasets about INRs. The expression of IFI27 was significantly negatively correlated with the CD4+ T-cell counts of PLWH, and the predictive efficiency of IFI27 level in distinguishing PLWH with poor immune recovery was also with significant power (AUC = 0.848). Conclusion The enhanced expression of IFI27 and the IFN response pathway are among the important immunological characteristics of INRs and exhibited promising efficiency as biomarkers for CD4+ T-cell recovery.
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Affiliation(s)
- Xiaosheng Liu
- Tsinghua-Peking Center for Life Sciences, Beijing, China.,Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China.,Department of Infectious Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Ling Lin
- Department of Infectious Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Lianfeng Lu
- Department of Infectious Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Xiaodi Li
- Department of Infectious Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Yang Han
- Department of Infectious Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Zhifeng Qiu
- Department of Infectious Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Xiaoxia Li
- Department of Infectious Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Yanling Li
- Department of Infectious Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Xiaojing Song
- Department of Infectious Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Wei Cao
- Department of Infectious Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Taisheng Li
- Tsinghua-Peking Center for Life Sciences, Beijing, China.,Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China.,Department of Infectious Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
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12
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Chlamydia trachomatis Stimulation Enhances HIV-1 Susceptibility through the Modulation of a Member of the Macrophage Inflammatory Proteins. J Invest Dermatol 2021; 142:1338-1348.e6. [PMID: 34662561 DOI: 10.1016/j.jid.2021.09.020] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 09/03/2021] [Accepted: 09/06/2021] [Indexed: 11/24/2022]
Abstract
Sexually transmitted infections such as Chlamydia trachomatis can enhance HIV-1 infection. However, the molecular mechanisms modulating the enhancement of HIV-1 infectivity and replication during HIV-1/sexually transmitted infections coinfection remain elusive. In this study, we performed an ex vivo infection of HIV-1 in PBMCs of C. trachomatis‒infected patients and observed a significant increase in HIV-1 p24 levels compared with those in cells from healthy donors. Similarly, C. trachomatis‒stimulated PBMCs from healthy donors showed enhanced susceptibility to HIV-1. C. trachomatis‒stimulated CD4 T cells also harbored more HIV-1 copy numbers. RNA sequencing data revealed the upregulation of CCL3L1/CCL3L3, a paralog of CCL3 in C. trachomatis‒stimulated CD4 T cells infected with HIV-1. Furthermore, an increase in CCL3L1/CCL3L3 expression levels correlated with HIV-1 replication in C. trachomatis‒stimulated cells. However, the addition of exogenous CCL3L1 reduces HIV-1 infection of healthy cells, indicating a dual role of CCL3L1 in HIV-1 infection. Further investigation revealed that a knockout of CCL3L1/CCL3L3 in Jurkat T cells rescued the increased susceptibility of C. trachomatis‒stimulated cells to HIV-1 infection. These results reveal a role for CCL3L1/CCL3L3 in enhancing HIV-1 replication and production and highlight a mechanism for the enhanced susceptibility to HIV-1 among C. trachomatis‒infected patients.
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13
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Warthi G, Fournier PE, Seligmann H. Identification of Noncanonical Transcripts Produced by Systematic Nucleotide Exchanges in HIV-Associated Centroblastic Lymphoma. DNA Cell Biol 2019; 39:1444-1448. [PMID: 31750730 DOI: 10.1089/dna.2019.5066] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Noncanonical transcriptions include transcriptions that systematically exchange nucleotides, also called bijective transformations or swinger transformations. Swinger transformation A↔T+C↔G recovers identities of 8 among 9 unknown RNAs differentially expressed in centroblastic lymphoma, a human immunodeficiency virus (HIV)-associated non-Hodgkin's lymphoma. The identified RNAs align with human genes with known anti-HIV1 or oncogenic activities. Function disruption through swinger-transformed transcription potentially enables avoiding antiviral responses and contributes to cancer induction.
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Affiliation(s)
- Ganesh Warthi
- IRD, APHM, Aix Marseille Univ, SSA, VITROME, IHU-Méditerranée Infection, Marseille, France.,IHU-Méditerranée Infection, Marseille, France
| | - Pierre-Edouard Fournier
- IRD, APHM, Aix Marseille Univ, SSA, VITROME, IHU-Méditerranée Infection, Marseille, France.,IHU-Méditerranée Infection, Marseille, France
| | - Hervé Seligmann
- The National Natural History Collections, The Hebrew University of Jerusalem, Jerusalem, Israel
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14
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Ma J, Zhao F, Su W, Li Q, Li J, Ji J, Deng Y, Zhou Y, Wang X, Yang H, Saksena NK, Kristiansen K, Wang H, Liu Y. Zinc finger and interferon-stimulated genes play a vital role in TB-IRIS following HAART in AIDS. Per Med 2018; 15:251-269. [PMID: 29984631 DOI: 10.2217/pme-2017-0084] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
AIM Co-infection in HIV-1 patients with Mycobacterium tuberculosis poses considerable risk of developing the immune reconstitution inflammatory syndrome (IRIS), especially upon the initiation of antiretroviral therapy (ART). Methodology & results: For transcriptomic analysis, peripheral blood mononuclear cells' whole gene expression was used from three patient groups: HIV+ (H), HIV-TB+ (HT), HIV-TB+ with IRIS (HTI). Pathway enrichment and functional analysis was performed before and after highly active ART. Genes in the interferon-stimulating and ZNF families maintained tight functional interaction and tilted the balance in favor of TB-IRIS. DISCUSSION & CONCLUSION The functional impairment of interaction between ZNF genes and interferon-stimulated genes, along with higher expression of S100A8/S100A9 genes possibly forms the genomic basis of TB-IRIS in a subset of HIV patients while on highly active ART.
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Affiliation(s)
- Jinmin Ma
- BGI-Shenzhen, Shenzhen 518083, PR China.,Laboratory of Genomics and Molecular Biomedicine, Department of Biology, University of Copenhagen, Copenhagen 2100, Denmark.,China National GeneBank, BGI-Shenzhen, Shenzhen 518120, PR China
| | - Fang Zhao
- Shenzhen Third People's Hospital, Shenzhen 518112, PR China
| | - Wei Su
- BGI-Shenzhen, Shenzhen 518083, PR China
| | - Qiongfang Li
- BGI-Shenzhen, Shenzhen 518083, PR China.,China National GeneBank, BGI-Shenzhen, Shenzhen 518120, PR China
| | - Jiandong Li
- BGI-Shenzhen, Shenzhen 518083, PR China.,China National GeneBank, BGI-Shenzhen, Shenzhen 518120, PR China
| | - Jingkai Ji
- BGI-Shenzhen, Shenzhen 518083, PR China.,China National GeneBank, BGI-Shenzhen, Shenzhen 518120, PR China
| | - Yong Deng
- Shenzhen Third People's Hospital, Shenzhen 518112, PR China
| | - Yang Zhou
- Shenzhen Third People's Hospital, Shenzhen 518112, PR China
| | - Xinfa Wang
- Shenzhen Third People's Hospital, Shenzhen 518112, PR China
| | - Huanming Yang
- BGI-Shenzhen, Shenzhen 518083, PR China.,James D. Watson Institute of Genome Science, Hangzhou 310007, PR China
| | - Nitin K Saksena
- BGI-Shenzhen, Shenzhen 518083, PR China.,IGO, 19a Boundary Street, Rushcutters Bay, Sydney, NSW, Australia
| | - Karsten Kristiansen
- Laboratory of Genomics and Molecular Biomedicine, Department of Biology, University of Copenhagen, Copenhagen 2100, Denmark
| | - Hui Wang
- BGI-Shenzhen, Shenzhen 518083, PR China.,Department of Engineering Science, University of Oxford, Oxford OX3 7DQ, UK
| | - Yingxia Liu
- Shenzhen Third People's Hospital, Shenzhen 518112, PR China
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15
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Zheng Y, Zheng X, Li S, Zhang H, Liu M, Yang Q, Zhang M, Sun Y, Wu J, Yu B. Identification of key genes and pathways in regulating immune‑induced diseases of dendritic cells by bioinformatic analysis. Mol Med Rep 2018; 17:7585-7594. [PMID: 29620200 PMCID: PMC5983944 DOI: 10.3892/mmr.2018.8834] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Accepted: 03/22/2018] [Indexed: 12/13/2022] Open
Abstract
Dendritic cells (DCs) serve crucial roles in the activation of the immune response, and imbalance in the activation or inhibition of DCs has been associated with an increased susceptibility to develop immune-induced diseases. However, the molecular mechanisms of regulating immune-induced diseases of DCs are not well understood. The aim of the present study was to identify the gene signatures and uncover the potential regulatory mechanisms in DCs. A total of 4 gene expression profiles (GSE52894, GSE72893, GSE75938 and GSE77969) were integrated and analyzed in depth. In total, 241 upregulated genes and 365 downregulated genes were detected. Gene ontology and pathway enrichment analysis showed that the differentially expressed genes (DEGs) were significantly enriched in the inflammatory response, the tumor necrosis factor (TNF) signaling pathway, the nuclear factor (NF)-κB signaling pathway and antigen processing. The top 10 hub genes were identified from the protein-protein analysis. The most significant 2 modules were filtered from the protein-protein network. The genes in 2 modules were involved in type I interferon signaling, the NF-κB signaling pathway and the TNF signaling pathway. Furthermore, the microRNA-mRNA network analysis was performed. The results of the present study revealed that the identified DEGs and pathways may improve our understanding of the mechanisms of the maturation of DCs, and the candidate hub genes that may be therapeutic targets for immune-induced diseases.
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Affiliation(s)
- Yang Zheng
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Xianghui Zheng
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Shuang Li
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Hanlu Zhang
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Mingyang Liu
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Qingyuan Yang
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Maomao Zhang
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Yong Sun
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Jian Wu
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Bo Yu
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
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16
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Lee SY, Choi BS, Yoon CH, Kang C, Kim K, Kim KC. Selection of biomarkers for HIV-1 latency by integrated analysis. Genomics 2018; 111:327-333. [PMID: 29454027 DOI: 10.1016/j.ygeno.2018.02.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2017] [Revised: 02/08/2018] [Accepted: 02/12/2018] [Indexed: 01/10/2023]
Abstract
A major obstacle in the treatment of human immunodeficiency virus type 1 (HIV-1) is its ability to establish latent infection. To find novel biomarkers associated with the mechanism of HIV-1 latent infection, we identified 70 candidate genes in HIV-1 latently infected cells through the integrated analysis in a previous study. It is important to select more effective biomarkers among 70 candidates and to verify the possibility of selected biomarkers for HIV-1 latency. We identified the 24 and 25 genes from 70 candidate genes in significantly enriched categories selected by Database for Annotation, Visualization and Integrated Discovery (DAVID) software and Gene Set Enrichment Analysis (GSEA) software, respectively. Also, we investigated genes regulated in both HIV-1 latently infected cell lines and PBMCs from HIV-1 infected patients and found the genes with a common pattern of expression levels in both cell lines and PBMCs. Consequently, we identified nine genes, APBB2, GMPR, IGF2BP3, LRP1, MAD2L2, MX1, OXR1, PTK2B, and TNFSF13B, via integrated analysis. Especially, APBB2 and MAD2L2 were identified in both DAVID and GSEA software. Our findings suggest that nine genes were identified via integrated analysis as potential biomarkers and in particular, APBB2 and MAD2L2 may be considered as more significant biomarkers for HIV-1 latency.
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Affiliation(s)
- Sun Young Lee
- Division of Viral Disease Research, Center for Infectious Diseases Research, Korea National Institute of Health, Chung-buk, Republic of Korea
| | - Byeong-Sun Choi
- Division of Viral Disease Research, Center for Infectious Diseases Research, Korea National Institute of Health, Chung-buk, Republic of Korea
| | - Cheol-Hee Yoon
- Division of Viral Disease Research, Center for Infectious Diseases Research, Korea National Institute of Health, Chung-buk, Republic of Korea
| | - Chun Kang
- Division of Viral Disease Research, Center for Infectious Diseases Research, Korea National Institute of Health, Chung-buk, Republic of Korea
| | - Kisoon Kim
- Division of Viral Disease Research, Center for Infectious Diseases Research, Korea National Institute of Health, Chung-buk, Republic of Korea
| | - Kyung-Chang Kim
- Division of Viral Disease Research, Center for Infectious Diseases Research, Korea National Institute of Health, Chung-buk, Republic of Korea.
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17
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Vermeire J, Roesch F, Sauter D, Rua R, Hotter D, Van Nuffel A, Vanderstraeten H, Naessens E, Iannucci V, Landi A, Witkowski W, Baeyens A, Kirchhoff F, Verhasselt B. HIV Triggers a cGAS-Dependent, Vpu- and Vpr-Regulated Type I Interferon Response in CD4 + T Cells. Cell Rep 2017; 17:413-424. [PMID: 27705790 DOI: 10.1016/j.celrep.2016.09.023] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2015] [Revised: 07/18/2016] [Accepted: 09/08/2016] [Indexed: 02/07/2023] Open
Abstract
Several pattern-recognition receptors sense HIV-1 replication products and induce type I interferon (IFN-I) production under specific experimental conditions. However, it is thought that viral sensing and IFN induction are virtually absent in the main target cells of HIV-1 in vivo. Here, we show that activated CD4+ T cells sense HIV-1 infection through the cytosolic DNA sensor cGAS and mount a bioactive IFN-I response. Efficient induction of IFN-I by HIV-1 infection requires proviral integration and is regulated by newly expressed viral accessory proteins: Vpr potentiates, while Vpu suppresses cGAS-dependent IFN-I induction. Furthermore, Vpr also amplifies innate sensing of HIV-1 infection in Vpx-treated dendritic cells. Our results identify cGAS as mediator of an IFN-I response to HIV-1 infection in CD4+ T cells and demonstrate that this response is modulated by the viral accessory proteins Vpr and Vpu. Thus, viral innate immune evasion is incomplete in the main target cells of HIV-1.
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Affiliation(s)
- Jolien Vermeire
- Department of Clinical Chemistry, Microbiology, and Immunology, Ghent University, 9000 Ghent, Belgium
| | - Ferdinand Roesch
- Département de Virologie, Unité Virus et Immunité, Institut Pasteur, 75015 Paris, France
| | - Daniel Sauter
- Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany
| | - Réjane Rua
- Département de Virologie, Unité Virus et Immunité, Institut Pasteur, 75015 Paris, France
| | - Dominik Hotter
- Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany
| | - Anouk Van Nuffel
- Department of Clinical Chemistry, Microbiology, and Immunology, Ghent University, 9000 Ghent, Belgium
| | - Hanne Vanderstraeten
- Department of Clinical Chemistry, Microbiology, and Immunology, Ghent University, 9000 Ghent, Belgium
| | - Evelien Naessens
- Department of Clinical Chemistry, Microbiology, and Immunology, Ghent University, 9000 Ghent, Belgium
| | - Veronica Iannucci
- Department of Clinical Chemistry, Microbiology, and Immunology, Ghent University, 9000 Ghent, Belgium
| | - Alessia Landi
- Department of Clinical Chemistry, Microbiology, and Immunology, Ghent University, 9000 Ghent, Belgium
| | - Wojciech Witkowski
- Department of Clinical Chemistry, Microbiology, and Immunology, Ghent University, 9000 Ghent, Belgium
| | - Ann Baeyens
- Department of Clinical Chemistry, Microbiology, and Immunology, Ghent University, 9000 Ghent, Belgium
| | - Frank Kirchhoff
- Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany
| | - Bruno Verhasselt
- Department of Clinical Chemistry, Microbiology, and Immunology, Ghent University, 9000 Ghent, Belgium.
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Garcia-Vidal E, Castellví M, Pujantell M, Badia R, Jou A, Gomez L, Puig T, Clotet B, Ballana E, Riveira-Muñoz E, Esté JA. Evaluation of the Innate Immune Modulator Acitretin as a Strategy To Clear the HIV Reservoir. Antimicrob Agents Chemother 2017; 61:e01368-17. [PMID: 28874382 PMCID: PMC5655051 DOI: 10.1128/aac.01368-17] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2017] [Accepted: 08/31/2017] [Indexed: 02/07/2023] Open
Abstract
The persistence of HIV despite suppressive antiretroviral therapy is a major roadblock to HIV eradication. Current strategies focused on inducing the expression of latent HIV fail to clear the persistent reservoir, prompting the development of new approaches for killing HIV-positive cells. Recently, acitretin was proposed as a pharmacological enhancer of the innate cellular defense network that led to virus reactivation and preferential death of infected cells. We evaluated the capacity of acitretin to reactivate and/or to facilitate immune-mediated clearance of HIV-positive cells. Acitretin did not induce HIV reactivation in latently infected cell lines (J-Lat and ACH-2). We could observe only modest induction of HIV reactivation by acitretin in latently green fluorescent protein-HIV-infected Jurkat cells, comparable to suboptimal concentrations of vorinostat, a known latency-reversing agent (LRA). Acitretin induction was insignificant, however, compared to optimal concentrations of LRAs. Acitretin failed to reactivate HIV in a model of latently infected primary CD4+ T cells but induced retinoic acid-inducible gene I (RIG-I) and mitochondrial antiviral signaling (MAVS) expression in infected and uninfected cells, confirming the role of acitretin as an innate immune modulator. However, this effect was not associated with selective killing of HIV-positive cells. In conclusion, acitretin-mediated stimulation of the RIG-I pathway for HIV reactivation is modest and thus may not meaningfully affect the HIV reservoir. Stimulation of the RIG-I-dependent interferon (IFN) cascade by acitretin may not significantly affect the selective destruction of latently infected HIV-positive cells.
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Affiliation(s)
- Edurne Garcia-Vidal
- AIDS Research Institute IrsiCaixa, AIDS Unit and Health Research Institute Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain
| | - Marc Castellví
- AIDS Research Institute IrsiCaixa, AIDS Unit and Health Research Institute Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain
| | - Maria Pujantell
- AIDS Research Institute IrsiCaixa, AIDS Unit and Health Research Institute Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain
| | - Roger Badia
- AIDS Research Institute IrsiCaixa, AIDS Unit and Health Research Institute Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain
| | - Antoni Jou
- AIDS Research Institute IrsiCaixa, AIDS Unit and Health Research Institute Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain
| | - Lucia Gomez
- AIDS Research Institute IrsiCaixa, AIDS Unit and Health Research Institute Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain
| | - Teresa Puig
- AIDS Research Institute IrsiCaixa, AIDS Unit and Health Research Institute Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain
| | - Bonaventura Clotet
- AIDS Research Institute IrsiCaixa, AIDS Unit and Health Research Institute Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain
| | - Ester Ballana
- AIDS Research Institute IrsiCaixa, AIDS Unit and Health Research Institute Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain
| | - Eva Riveira-Muñoz
- AIDS Research Institute IrsiCaixa, AIDS Unit and Health Research Institute Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain
| | - José A Esté
- AIDS Research Institute IrsiCaixa, AIDS Unit and Health Research Institute Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain
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19
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Wong YY, Johnson B, Friedrich TC, Trepanier LA. Hepatic expression profiles in retroviral infection: relevance to drug hypersensitivity risk. Pharmacol Res Perspect 2017; 5:e00312. [PMID: 28603631 PMCID: PMC5464341 DOI: 10.1002/prp2.312] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2017] [Accepted: 03/13/2017] [Indexed: 12/11/2022] Open
Abstract
HIV‐infected patients show a markedly increased risk of delayed hypersensitivity (HS) reactions to potentiated sulfonamide antibiotics (trimethoprim/sulfamethoxazole or TMP/SMX). Some studies have suggested altered SMX biotransformation in HIV infection, but hepatic biotransformation pathways have not been evaluated directly. Systemic lupus erythematosus (SLE) is another chronic inflammatory disease with a higher incidence of sulfonamide HS, but it is unclear whether retroviral infection and SLE share risk factors for drug HS. We hypothesized that retroviral infection would lead to dysregulation of hepatic pathways of SMX biotransformation, as well as pathway alterations in common with SLE that could contribute to drug HS risk. We characterized hepatic expression profiles and enzymatic activities in an SIV‐infected macaque model of retroviral infection, and found no evidence for dysregulation of sulfonamide drug biotransformation pathways. Specifically, NAT1,NAT2,CYP2C8,CYP2C9,CYB5R3,MARC1/2, and glutathione‐related genes (GCLC,GCLM,GSS,GSTM1, and GSTP1) were not differentially expressed in drug naïve SIVmac239‐infected male macaques compared to age‐matched controls, and activities for SMX N‐acetylation and SMX hydroxylamine reduction were not different. However, multiple genes that are reportedly over‐expressed in SLE patients were also up‐regulated in retroviral infection, to include enhanced immunoproteasomal processing and presentation of antigens as well as up‐regulation of gene clusters that may be permissive to autoimmunity. These findings support the hypothesis that pathways downstream from drug biotransformation may be primarily important in drug HS risk in HIV infection.
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Affiliation(s)
- Yat Yee Wong
- Department of Medical Sciences School of Veterinary Medicine Madison Wisconsin
| | - Brian Johnson
- Molecular and Environmental Toxicology Center School of Medicine and Public Health University of Wisconsin-Madison Madison Wisconsin
| | - Thomas C Friedrich
- Department of Pathobiological Sciences School of Veterinary Medicine Madison Wisconsin.,AIDS Vaccine Research Laboratory Wisconsin National Primate Research Center Madison Wisconsin
| | - Lauren A Trepanier
- Department of Medical Sciences School of Veterinary Medicine Madison Wisconsin
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Virion-Associated Vpr Alleviates a Postintegration Block to HIV-1 Infection of Dendritic Cells. J Virol 2017; 91:JVI.00051-17. [PMID: 28424288 DOI: 10.1128/jvi.00051-17] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2017] [Accepted: 04/16/2017] [Indexed: 01/23/2023] Open
Abstract
Viral protein R (Vpr) is an HIV-1 accessory protein whose function remains poorly understood. In this report, we sought to determine the requirement of Vpr for facilitating HIV-1 infection of monocyte-derived dendritic cells (MDDCs), one of the first cell types to encounter virus in the peripheral mucosal tissues. In this report, we characterize a significant restriction of Vpr-deficient virus replication and spread in MDDCs alone and in cell-to-cell spread in MDDC-CD4+ T cell cocultures. This restriction of HIV-1 replication in MDDCs was observed in a single round of virus replication and was rescued by the expression of Vpr in trans in the incoming virion. Interestingly, infections of MDDCs with viruses that encode Vpr mutants unable to interact with either the DCAF1/DDB1 E3 ubiquitin ligase complex or a host factor hypothesized to be targeted for degradation by Vpr also displayed a significant replication defect. While the extent of proviral integration in HIV-1-infected MDDCs was unaffected by the absence of Vpr, the transcriptional activity of the viral long terminal repeat (LTR) from Vpr-deficient proviruses was significantly reduced. Together, these results characterize a novel postintegration restriction of HIV-1 replication in MDDCs and show that the interaction of Vpr with the DCAF1/DDB1 E3 ubiquitin ligase complex and the yet-to-be-identified host factor might alleviate this restriction by inducing transcription from the viral LTR. Taken together, these findings identify a robust in vitro cell culture system that is amenable to addressing mechanisms underlying Vpr-mediated enhancement of HIV-1 replication.IMPORTANCE Despite decades of work, the function of the HIV-1 protein Vpr remains poorly understood, primarily due to the lack of an in vitro cell culture system that demonstrates a deficit in replication upon infection with viruses in the absence of Vpr. In this report, we describe a novel cell infection system that utilizes primary human dendritic cells, which display a robust decrease in viral replication upon infection with Vpr-deficient HIV-1. We show that this replication difference occurs in a single round of infection and is due to decreased transcriptional output from the integrated viral genome. Viral transcription could be rescued by virion-associated Vpr. Using mutational analysis, we show that domains of Vpr involved in binding to the DCAF1/DDB1/E3 ubiquitin ligase complex and prevention of cell cycle progression into mitosis are required for LTR-mediated viral expression, suggesting that the evolutionarily conserved G2 cell cycle arrest function of Vpr is essential for HIV-1 replication.
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Qu H, Li J, Yang L, Sun L, Liu W, He H. Influenza A Virus-induced expression of ISG20 inhibits viral replication by interacting with nucleoprotein. Virus Genes 2016; 52:759-767. [PMID: 27342813 DOI: 10.1007/s11262-016-1366-2] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Accepted: 06/18/2016] [Indexed: 11/25/2022]
Abstract
Influenza A virus (IAV) is an important pathogen that has a wide range of hosts and represents a threat to the health of humans and several animal species. IAV infection can induce the transcription of many genes in the host. In the present study, we demonstrated for the first time that three different strains of H1N1 IAV induce the expression of an IFN-stimulated gene, ISG20. We determined the antiviral activity of ISG20 against IAV because ISG20 inhibited viral protein expression and reduced the progeny viral titer dependent upon its exonuclease activity. To elucidate the detailed mechanism of ISG20, we further demonstrated that ISG20 impairs the polymerase activity and inhibits both the replication and transcription levels of the M1 and NP genes. Notably, we identified that ISG20 colocalizes and interacts with NP during IAV infection, while exonuclease-inactive mutant ISG20 lacked association with NP, indicating that ISG20 inhibits IAV replication by interacting with NP. Together, these data provide a detailed explanation for the specific antiviral action of ISG20 and suggest that ISG20 may act as a promising antiviral drug candidate against IAV.
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Affiliation(s)
- Hongren Qu
- National Research Center for Wildlife-Borne Diseases, Institute of Zoology, Chinese Academy of Sciences, 100101, Beijing, China
| | - Jing Li
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, 100101, Beijing, China
| | - Limin Yang
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, 100101, Beijing, China
| | - Lei Sun
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, 100101, Beijing, China
| | - Wenjun Liu
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, 100101, Beijing, China.
| | - Hongxuan He
- National Research Center for Wildlife-Borne Diseases, Institute of Zoology, Chinese Academy of Sciences, 100101, Beijing, China.
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22
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Xie DY, Wang SM, Yang JM, Wang LH, Chen HY, Huai C, Shang J, Mao Q, Lei CL, Luo GH, Qian J, Lu DR. IFIT1 polymorphisms predict interferon-α treatment efficiency for hepatitis B virus infection. World J Gastroenterol 2016; 22:9813-9821. [PMID: 27956805 PMCID: PMC5124986 DOI: 10.3748/wjg.v22.i44.9813] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Revised: 08/19/2016] [Accepted: 09/08/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the association between interferon-induced protein with tetratricopeptide repeats 1 (IFIT1) polymorphisms and interferon-α (IFNα) treatment efficiency among Chinese hepatitis B virus (HBV) infection patients.
METHODS Two hundred and twenty five newly diagnosed chronic hepatitis B (CHB) patients were enrolled in the study. All of these patients received IFNα treatment for a course of 48 wk, and were followed up for 24 wk after the treatment was end. Clinical information about virological response, hepatitis B e antigen (HBeAg) seroconversion rate and combined response at the end of the treatment, as well as the sustained response by the time of following up 24 wk after the treatment, was collected. Four tag-single nucleotide polymorphisms (SNPs) of IFIT1 were selected and assessed for their association with these clinical outcomes.
RESULTS At the end of the treatment, HBeAg seroconversion was observed in 27.1% patients. Thirty-six point nine percent patients achieved virological response, and 15.6% patients exhibited combined response. Sustained response was obtained in 26.2% patients. The main HBV genotype of the study was genotype B. Patients who infected with HBV genotype B or C showed better treatment efficiency, no matter which clinical outcome was considered. Among the four SNPs assessed, rs303218 (A > G) was found to be significantly associated with the end point virological response when assuming additive model [OR = 0.64 (95%CI: 0.42-0.96), P = 0.032]. Patients who carried rs303218 GG genotype had a rather higher rate of achieving virological response (response rate: 52%, OR = 0.40, 95%CI: 0.18-0.91; P = 0.028) when compared to those had AA genotype (response rate: 27%). The most significant interaction was observed in patients who had relative lower baseline aspartate transaminase. No association between SNPs and HBeAg seroconversion, combined response or sustained response was observed.
CONCLUSION IFIT1 involves in the regulation of IFNα treatment for CHB and its polymorphism rs303218 can predict the end point virological response. The finding requires further validation.
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23
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Pujantell M, Badia R, Ramirez C, Puig T, Clotet B, Ballana E, Esté JA, Riveira-Muñoz E. Long-term HIV-1 infection induces an antiviral state in primary macrophages. Antiviral Res 2016; 133:145-55. [PMID: 27510577 DOI: 10.1016/j.antiviral.2016.08.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Revised: 07/27/2016] [Accepted: 08/05/2016] [Indexed: 12/23/2022]
Abstract
HIV-1 infection is thought to impair type I interferon (IFN-I) production in macrophages, a cell type that is also relatively resistant to HIV-1 cytotoxic effects. Here, we show that monocyte differentiation into macrophages by M-CSF led to cell proliferation and susceptibility to HIV-1 infection that induced cell cycle arrest and increased cell death. Established HIV-1 infection of monocyte-derived macrophages induced the upregulation of the pattern recognition receptors MDA5 and Rig-I that serve as virus sensors; production of interferon-β, and transcription of interferon-stimulated genes including CXCL10. Infected macrophages showed increased expression of p21 and subsequent inactivation of cyclin-CDK2 activity leading to a hypo-phosphorylated active retinoblastoma protein (pRb) and deactivation of E2F1-dependent transcription and CDK1 downregulation. Additionally, HIV-1 infection limited deoxynucleotide pool by downregulation of the ribonucleotide reductase subunit R2 (RNR2) and reactivation of the HIV-1 restriction factor SAMHD1 together with increased cell death. In conclusion, HIV-1 induced an innate antiviral mechanism associated to IFN-I production, interferon stimulated gene activation, and p21-mediated G2/M arrest leading to elevated levels of cell death in monocyte derived macrophages. Upregulation of MDA5 and Rig-I may serve as targets for the development of antiviral strategies leading to the elimination of HIV-1 infected cells.
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Affiliation(s)
- Maria Pujantell
- AIDS Research Institute - IrsiCaixa and Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain
| | - Roger Badia
- AIDS Research Institute - IrsiCaixa and Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain
| | - Cristina Ramirez
- AIDS Research Institute - IrsiCaixa and Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain
| | - Teresa Puig
- AIDS Research Institute - IrsiCaixa and Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain
| | - Bonaventura Clotet
- AIDS Research Institute - IrsiCaixa and Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain
| | - Ester Ballana
- AIDS Research Institute - IrsiCaixa and Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain
| | - José A Esté
- AIDS Research Institute - IrsiCaixa and Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.
| | - Eva Riveira-Muñoz
- AIDS Research Institute - IrsiCaixa and Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain
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Vpr Enhances Tumor Necrosis Factor Production by HIV-1-Infected T Cells. J Virol 2015; 89:12118-30. [PMID: 26401039 DOI: 10.1128/jvi.02098-15] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2015] [Accepted: 09/16/2015] [Indexed: 02/06/2023] Open
Abstract
UNLABELLED The HIV-1 accessory protein Vpr displays different activities potentially impacting viral replication, including the arrest of the cell cycle in the G2 phase and the stimulation of apoptosis and DNA damage response pathways. Vpr also modulates cytokine production by infected cells, but this property remains partly characterized. Here, we investigated the effect of Vpr on the production of the proinflammatory cytokine tumor necrosis factor (TNF). We report that Vpr significantly increases TNF secretion by infected lymphocytes. De novo production of Vpr is required for this effect. Vpr mutants known to be defective for G2 cell cycle arrest induce lower levels of TNF secretion, suggesting a link between these two functions. Silencing experiments and the use of chemical inhibitors further implicated the cellular proteins DDB1 and TAK1 in this activity of Vpr. TNF secreted by HIV-1-infected cells triggers NF-κB activity in bystander cells and allows viral reactivation in a model of latently infected cells. Thus, the stimulation of the proinflammatory pathway by Vpr may impact HIV-1 replication in vivo. IMPORTANCE The role of the HIV-1 accessory protein Vpr remains only partially characterized. This protein is important for viral pathogenesis in infected individuals but is dispensable for viral replication in most cell culture systems. Some of the functions described for Vpr remain controversial. In particular, it remains unclear whether Vpr promotes or instead prevents proinflammatory and antiviral immune responses. In this report, we show that Vpr promotes the release of TNF, a proinflammatory cytokine associated with rapid disease progression. Using Vpr mutants or inhibiting selected cellular genes, we show that the cellular proteins DDB1 and TAK1 are involved in the release of TNF by HIV-infected cells. This report provides novel insights into how Vpr manipulates TNF production and helps clarify the role of Vpr in innate immune responses and inflammation.
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