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Dr. Sijia He received her Ph.D. in clinical laboratory diagnostics from China Medical University. She has conducted research in immunology, virology, and molecular biology, with a particular interest in HIV infection and human immune responses. Dr. He is currently conducting research as a postdoctoral research fellow in the NCBID at George Mason University. She continues her research on cell signal transduction involved in latent HIV infection and the antiviral mechanisms of host restriction factors that how PSGL-1 hinders HIV infection of target cells.
Summary Although peripheral B cell dysfunction in early HIV infection is established, how B cell subsets are altered by HIV infection is poorly understood. While investigating B cell subsets among individuals recently infected with HIV, we observe an accumulation of CD27−CD38+ B cells and find that these cells can directly facilitate HIV infection of primary CD4+ T cells in vitro. Comprehensive analyses of the phenotype, function, and transcriptome of the CD27−CD38+ B cell subset is conducted compared with memory and naive B cells. We find that the CD27−CD38+ B cells exhibit a transitional B cell phenotype and an extremely high turnover rate. Importantly, individuals with higher proportions of CD27−CD38+ B cells during early HIV infection tend to become rapid progressors in the chronic infection stage. In this study, we identify a peripheral transitional B cell subset that accumulates during early HIV infection and may contribute to disease progression.
Yajing Fu; Zining Zhang; Zhijun Yang; Yongjun Jiang; Xiaoxu Han; Junjie Xu; Zhenxing Chu; Haibo Ding; Sijia He; Hong Shang. CD27−CD38+ B cells accumulated in early HIV infection exhibit transitional profile and promote HIV disease progression. Cell Reports 2021, 36, 1 .
AMA StyleYajing Fu, Zining Zhang, Zhijun Yang, Yongjun Jiang, Xiaoxu Han, Junjie Xu, Zhenxing Chu, Haibo Ding, Sijia He, Hong Shang. CD27−CD38+ B cells accumulated in early HIV infection exhibit transitional profile and promote HIV disease progression. Cell Reports. 2021; 36 (2):1.
Chicago/Turabian StyleYajing Fu; Zining Zhang; Zhijun Yang; Yongjun Jiang; Xiaoxu Han; Junjie Xu; Zhenxing Chu; Haibo Ding; Sijia He; Hong Shang. 2021. "CD27−CD38+ B cells accumulated in early HIV infection exhibit transitional profile and promote HIV disease progression." Cell Reports 36, no. 2: 1.
Mucins and mucin-like molecules are highly glycosylated, high-molecular-weight cell surface proteins that possess a semi-rigid and highly extended extracellular domain. P-selectin glycoprotein ligand-1 (PSGL-1), a mucin-like glycoprotein, has recently been found to restrict HIV-1 infectivity through virion incorporation that sterically hinders virus particle attachment to target cells. Here, we report the identification of a family of antiviral cellular proteins, named the Surface-Hinged, Rigidly-Extended Killer (SHREK) family of virion inactivators (PSGL-1, CD43, TIM-1, CD34, PODXL1, PODXL2, CD164, MUC1, MUC4, and TMEM123) that share similar structural characteristics with PSGL-1. We demonstrate that SHREK proteins block HIV-1 infectivity by inhibiting virus particle attachment to target cells. In addition, we demonstrate that SHREK proteins are broad-spectrum host antiviral factors that block the infection of diverse viruses such as influenza A. Furthermore, we demonstrate that a subset of SHREKs also blocks the infectivity of a hybrid alphavirus-SARS-CoV-2 (Ha-CoV-2) pseudovirus. These results suggest that SHREK proteins may be a part of host innate immunity against enveloped viruses.
Deemah Dabbagh; Sijia He; Brian Hetrick; Linda Chilin; Ali Andalibi; Yuntao Wu. Identification of the SHREK Family of Proteins as Broad-Spectrum Host Antiviral Factors. Viruses 2021, 13, 832 .
AMA StyleDeemah Dabbagh, Sijia He, Brian Hetrick, Linda Chilin, Ali Andalibi, Yuntao Wu. Identification of the SHREK Family of Proteins as Broad-Spectrum Host Antiviral Factors. Viruses. 2021; 13 (5):832.
Chicago/Turabian StyleDeemah Dabbagh; Sijia He; Brian Hetrick; Linda Chilin; Ali Andalibi; Yuntao Wu. 2021. "Identification of the SHREK Family of Proteins as Broad-Spectrum Host Antiviral Factors." Viruses 13, no. 5: 832.
P-selectin glycoprotein ligand-1 (PSGL-1) is a cell surface glycoprotein that binds to P-, E-, and L-selectins to mediate the tethering and rolling of immune cells on the surface of the endothelium for cell migration into inflamed tissues. PSGL-1 has been identified as an interferon-γ (INF-γ)-regulated factor that restricts HIV-1 infectivity, and has recently been found to possess broad-spectrum antiviral activities. Here we report that the expression of PSGL-1 in virus-producing cells impairs the incorporation of SARS-CoV and SARS-CoV-2 spike (S) glycoproteins into pseudovirions and blocks pseudovirus attachment and infection of target cells. These findings suggest that PSGL-1 may potentially inhibit coronavirus replication in PSGL-1+ cells
Sijia He; Abdul A. Waheed; Brian Hetrick; Deemah Dabbagh; Ivan V. Akhrymuk; Kylene Kehn-Hall; Eric O. Freed; Yuntao Wu. PSGL-1 Inhibits the Incorporation of SARS-CoV and SARS-CoV-2 Spike Glycoproteins into Pseudovirions and Impairs Pseudovirus Attachment and Infectivity. Viruses 2020, 13, 46 .
AMA StyleSijia He, Abdul A. Waheed, Brian Hetrick, Deemah Dabbagh, Ivan V. Akhrymuk, Kylene Kehn-Hall, Eric O. Freed, Yuntao Wu. PSGL-1 Inhibits the Incorporation of SARS-CoV and SARS-CoV-2 Spike Glycoproteins into Pseudovirions and Impairs Pseudovirus Attachment and Infectivity. Viruses. 2020; 13 (1):46.
Chicago/Turabian StyleSijia He; Abdul A. Waheed; Brian Hetrick; Deemah Dabbagh; Ivan V. Akhrymuk; Kylene Kehn-Hall; Eric O. Freed; Yuntao Wu. 2020. "PSGL-1 Inhibits the Incorporation of SARS-CoV and SARS-CoV-2 Spike Glycoproteins into Pseudovirions and Impairs Pseudovirus Attachment and Infectivity." Viruses 13, no. 1: 46.
Objective To provide a comprehensive and systematic analysis of demographic characteristics, clinical symptoms, laboratory findings and imaging features of coronavirus disease 2019 (COVID‐19) in pediatric patients. Methods A meta‐analysis was carried out to identify studies on COVID‐19 from December 25, 2019 to April 30, 2020. Results A total of 48 studies with 5829 pediatric patients were included. Children at all ages were at risk for COVID‐19. The main illness classification ranged as: 20% (95% CI: 14 to 26%, I2=91.4%) asymptomatic, 33% (95% CI: 23 to 43%, I2=95.6%) mild and 51% (95% CI: 42 to 61%, I2=93.4%) moderate. The typical clinical manifestations were fever 51% (95% CI: 45 to 57%, I2=78.9%) and cough 41% (95% CI: 35 to 47%, I2=81.0%). The common laboratory findings were normal white blood cell 69% (95% CI: 64 to 75%, I2=58.5%), lymphopenia 16% (95% CI: 11 to 21%, I2=76.9%) and elevated creatine‐kinase MB (CK‐MB) 37% (95% CI: 25 to 48%, I2=59.0%). The frequent imaging features were normal images 41% (95% CI: 30 to 52%, I2=93.4%) and ground‐glass opacity 36% (95% CI: 25 to 47%, I2=92.9%). Among children under 1‐year old, critical cases account for 14% (95% CI: 13 to 34%, I2=37.3%) that should be of concern. In addition, vomiting occurred in 33% (95% CI: 18 to 67%, I2=0.0%) cases that may also need attention. Conclusions Pediatric patients with COVID‐19 may experience milder illness with atypical clinical manifestations and rare lymphopenia. High incidence of critical illness and vomiting symptoms reward attention in children under 1‐year old. This article is protected by copyright. All rights reserved.
Xiaojian Cui; Zhihu Zhao; Tongqiang Zhang; Wei Guo; Wenwei Guo; Jiafeng Zheng; Jiayi Zhang; Cuicui Dong; Ren Na; Lisheng Zheng; Wenliang Li; Zihui Liu; Jia Ma; Jinhu Wang; Sijia He; Yongsheng Xu; Ping Si; Yongming Shen; Chunquan Cai. A systematic review and meta‐analysis of children with coronavirus disease 2019 (COVID‐19). Journal of Medical Virology 2020, 93, 1057 -1069.
AMA StyleXiaojian Cui, Zhihu Zhao, Tongqiang Zhang, Wei Guo, Wenwei Guo, Jiafeng Zheng, Jiayi Zhang, Cuicui Dong, Ren Na, Lisheng Zheng, Wenliang Li, Zihui Liu, Jia Ma, Jinhu Wang, Sijia He, Yongsheng Xu, Ping Si, Yongming Shen, Chunquan Cai. A systematic review and meta‐analysis of children with coronavirus disease 2019 (COVID‐19). Journal of Medical Virology. 2020; 93 (2):1057-1069.
Chicago/Turabian StyleXiaojian Cui; Zhihu Zhao; Tongqiang Zhang; Wei Guo; Wenwei Guo; Jiafeng Zheng; Jiayi Zhang; Cuicui Dong; Ren Na; Lisheng Zheng; Wenliang Li; Zihui Liu; Jia Ma; Jinhu Wang; Sijia He; Yongsheng Xu; Ping Si; Yongming Shen; Chunquan Cai. 2020. "A systematic review and meta‐analysis of children with coronavirus disease 2019 (COVID‐19)." Journal of Medical Virology 93, no. 2: 1057-1069.
An epidemic of coronavirus disease 2019 (COVID‐19) has been spreading worldwide. With the rapid increase in the number of infections, children with COVID‐19 appear to be rising. Most research findings regarding adult cases, which are not always transferrable to children. Evidence‐based studies are still expected to formulate clinical decisions for pediatric patients. In this review, we evaluated the demographic, clinical, laboratory and imaging features from 2,597 pediatric patients of COVID‐19 that reported recently. We found that even lymphopenia was the most common lab finding in adults, it infrequently occurred in children (9.8%). Moreover, elevated creatine kinase MB isoenzyme (CK‐MB) was much more commonly observed in children (27.0%) than that in adults, suggesting that heart injury would be more likely to happen in pediatric patients. Our analysis may contribute to determine the spectrum of disease in children, as well as to develop strategies to control the disease transmission. This article is protected by copyright. All rights reserved.
Xiaojian Cui; Tongqiang Zhang; Jiafeng Zheng; Jiayi Zhang; Ping Si; Yongsheng Xu; Wei Guo; Zihui Liu; Wenliang Li; Jia Ma; Cuicui Dong; Yongming Shen; Chunquan Cai; Sijia He. Children with coronavirus disease 2019: A review of demographic, clinical, laboratory, and imaging features in pediatric patients. Journal of Medical Virology 2020, 92, 1501 -1510.
AMA StyleXiaojian Cui, Tongqiang Zhang, Jiafeng Zheng, Jiayi Zhang, Ping Si, Yongsheng Xu, Wei Guo, Zihui Liu, Wenliang Li, Jia Ma, Cuicui Dong, Yongming Shen, Chunquan Cai, Sijia He. Children with coronavirus disease 2019: A review of demographic, clinical, laboratory, and imaging features in pediatric patients. Journal of Medical Virology. 2020; 92 (9):1501-1510.
Chicago/Turabian StyleXiaojian Cui; Tongqiang Zhang; Jiafeng Zheng; Jiayi Zhang; Ping Si; Yongsheng Xu; Wei Guo; Zihui Liu; Wenliang Li; Jia Ma; Cuicui Dong; Yongming Shen; Chunquan Cai; Sijia He. 2020. "Children with coronavirus disease 2019: A review of demographic, clinical, laboratory, and imaging features in pediatric patients." Journal of Medical Virology 92, no. 9: 1501-1510.
P-selectin glycoprotein ligand-1 (PSGL-1) is a cell surface glycoprotein that binds to P-, E-, and L-selectins to mediate the tethering and rolling of immune cells on the surface of the endothelium for cell migration into inflamed tissues. PSGL-1 has been identified as an interferon-γ (INF-γ)-regulated factor that restricts HIV-1 infectivity, and has recently been found to possess broad-spectrum antiviral activities. Here we report that the expression of PSGL-1 in virus-producing cells impairs the incorporation of SARS-CoV and SARS-CoV-2 spike (S) glycoproteins into pseudovirions and blocks virus attachment and infection of target cells. These findings suggest that PSGL-1 may potentially inhibit coronavirus replication in PSGL-1+ cells.
Sijia He; Abdul A. Waheed; Brian Hetrick; Deemah Dabbagh; Ivan V. Akhrymuk; Kylene Kehn-Hall; Eric O. Freed; Yuntao Wu. PSGL-1 inhibits the virion incorporation of SARS-CoV and SARS-CoV-2 spike glycoproteins and impairs virus attachment and infectivity. 2020, 1 .
AMA StyleSijia He, Abdul A. Waheed, Brian Hetrick, Deemah Dabbagh, Ivan V. Akhrymuk, Kylene Kehn-Hall, Eric O. Freed, Yuntao Wu. PSGL-1 inhibits the virion incorporation of SARS-CoV and SARS-CoV-2 spike glycoproteins and impairs virus attachment and infectivity. . 2020; ():1.
Chicago/Turabian StyleSijia He; Abdul A. Waheed; Brian Hetrick; Deemah Dabbagh; Ivan V. Akhrymuk; Kylene Kehn-Hall; Eric O. Freed; Yuntao Wu. 2020. "PSGL-1 inhibits the virion incorporation of SARS-CoV and SARS-CoV-2 spike glycoproteins and impairs virus attachment and infectivity." , no. : 1.
P-selectin glycoprotein ligand-1 (PSGL-1) is a dimeric, mucin-like, 120-kDa glycoprotein that binds to P-, E-, and L-selectins. PSGL-1 is expressed primarily on the surface of lymphoid and myeloid cells and is up-regulated during inflammation to mediate leukocyte tethering and rolling on the surface of endothelium for migration into inflamed tissues. Although it has been reported that PSGL-1 expression inhibits HIV-1 replication, the mechanism of PSGL-1–mediated anti-HIV activity remains to be elucidated. Here we report that PSGL-1 in virions blocks the infectivity of HIV-1 particles by preventing the binding of particles to target cells. This inhibitory activity is independent of the viral glycoprotein present on the virus particle; the binding of particles bearing the HIV-1 envelope glycoprotein or vesicular stomatitis virus G glycoprotein or even lacking a viral glycoprotein is impaired by PSGL-1. Mapping studies show that the extracellular N-terminal domain of PSGL-1 is necessary for its anti–HIV-1 activity, and that the PSGL-1 cytoplasmic tail contributes to inhibition. In addition, we demonstrate that the PSGL-1–related monomeric E-selectin–binding glycoprotein CD43 also effectively blocks HIV-1 infectivity. HIV-1 infection, or expression of either Vpu or Nef, down-regulates PSGL-1 from the cell surface; expression of Vpu appears to be primarily responsible for enabling the virus to partially escape PSGL-1–mediated restriction. Finally, we show that PSGL-1 inhibits the infectivity of other viruses, such as murine leukemia virus and influenza A virus. These findings demonstrate that PSGL-1 is a broad-spectrum antiviral host factor with a unique mechanism of action.
Yajing Fu; Sijia He; Abdul A. Waheed; Deemah Dabbagh; Zheng Zhou; Benjamin Trinité; Zhao Wang; Jieshi Yu; Dan Wang; Feng Li; David N. Levy; Hong Shang; Eric O. Freed; Yuntao Wu. PSGL-1 restricts HIV-1 infectivity by blocking virus particle attachment to target cells. Proceedings of the National Academy of Sciences 2020, 117, 9537 -9545.
AMA StyleYajing Fu, Sijia He, Abdul A. Waheed, Deemah Dabbagh, Zheng Zhou, Benjamin Trinité, Zhao Wang, Jieshi Yu, Dan Wang, Feng Li, David N. Levy, Hong Shang, Eric O. Freed, Yuntao Wu. PSGL-1 restricts HIV-1 infectivity by blocking virus particle attachment to target cells. Proceedings of the National Academy of Sciences. 2020; 117 (17):9537-9545.
Chicago/Turabian StyleYajing Fu; Sijia He; Abdul A. Waheed; Deemah Dabbagh; Zheng Zhou; Benjamin Trinité; Zhao Wang; Jieshi Yu; Dan Wang; Feng Li; David N. Levy; Hong Shang; Eric O. Freed; Yuntao Wu. 2020. "PSGL-1 restricts HIV-1 infectivity by blocking virus particle attachment to target cells." Proceedings of the National Academy of Sciences 117, no. 17: 9537-9545.
Coronavirus Disease 2019 (COVID‐19) is a newly emerging infectious disease caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). After its first occurrence in Wuhan of China from December 2019, COVID‐19 rapidly spread around the world. According to the World Health Organization (WHO) statement on March 13, 2020, there had been over 132,500 confirmed cases globally. Nevertheless, the case reports of children are rare, which result in the lack of evidence for preventing and controlling of children's infection. Here, we report 3 cases of SARS‐CoV‐2 infected children diagnosed from February 3 to February 17, 2020 in Tianjin, China. All of these three cases experienced mild illness and recovered soon after treatment, with the nucleic acid of throat swab turning negative within 14, 11, 7 days after diagnosis respectively. However, after been discharged, all the three cases were tested SARS‐CoV‐2 positive in the stool samples within 10 days, in spite of their remained negative nucleic acid in throat swab specimens. Therefore, it is necessary to be aware of the possibility of fecal‐oral transmission of SARS‐CoV‐2 infection, especially for children cases. This article is protected by copyright. All rights reserved.
Tongqiang Zhang; Xiaojian Cui; Xue Zhao; Jinhu Wang; Jiafeng Zheng; Guifen Zheng; Wei Guo; Chunquan Cai; Sijia He; Yongsheng Xu. Detectable SARS‐CoV‐2 viral RNA in feces of three children during recovery period of COVID‐19 pneumonia. Journal of Medical Virology 2020, 92, 909 -914.
AMA StyleTongqiang Zhang, Xiaojian Cui, Xue Zhao, Jinhu Wang, Jiafeng Zheng, Guifen Zheng, Wei Guo, Chunquan Cai, Sijia He, Yongsheng Xu. Detectable SARS‐CoV‐2 viral RNA in feces of three children during recovery period of COVID‐19 pneumonia. Journal of Medical Virology. 2020; 92 (7):909-914.
Chicago/Turabian StyleTongqiang Zhang; Xiaojian Cui; Xue Zhao; Jinhu Wang; Jiafeng Zheng; Guifen Zheng; Wei Guo; Chunquan Cai; Sijia He; Yongsheng Xu. 2020. "Detectable SARS‐CoV‐2 viral RNA in feces of three children during recovery period of COVID‐19 pneumonia." Journal of Medical Virology 92, no. 7: 909-914.
HIV infection causes CD4 depletion and immune deficiency. The virus infects CD4 T cells through binding to CD4 and one of the chemokine coreceptors, CXCR4 (X4) or CCR5 (R5). It has also been known that HIV tropism switch, from R5 to X4, is associated with rapid CD4 depletion, suggesting a key role of viral factors in driving CD4 depletion. However, the virological driver for HIV-mediated CD4 depletion has not been fully elucidated. We hypothesized that HIV-mediated chemokine coreceptor signaling, particularly chronic signaling through CXCR4, plays a major role in CD4 dysfunction and depletion; we also hypothesized that there is an R5X4 signaling (R5X4sig) viral subspecies, evolving from the natural replication course of R5-utilizing viruses, that is responsible for CD4 T cell depletion in R5 virus infection. To gain traction for our hypothesis, in this review, we discuss a recent finding from Cui and co-authors who described the rapid tropism switch and high pathogenicity of an HIV-1 R5 virus, CRF01_AE. We speculate that CRF01_AE may be the hypothetical R5X4sig viral species that is rapidly evolving towards the X4 phenotype. We also attempt to discuss the intricate relationships between HIV-mediated chemokine coreceptor signaling, viral tropism switch and HIV-mediated CD4 depletion, in hopes of providing a deeper understanding of HIV pathogenesis in blood CD4 T cells.
Sijia He. Relationships Between HIV-Mediated Chemokine Coreceptor Signaling, Cofilin Hyperactivation, Viral Tropism Switch and HIV-Mediated CD4 Depletion. Current HIV Research 2020, 17, 388 -396.
AMA StyleSijia He. Relationships Between HIV-Mediated Chemokine Coreceptor Signaling, Cofilin Hyperactivation, Viral Tropism Switch and HIV-Mediated CD4 Depletion. Current HIV Research. 2020; 17 (6):388-396.
Chicago/Turabian StyleSijia He. 2020. "Relationships Between HIV-Mediated Chemokine Coreceptor Signaling, Cofilin Hyperactivation, Viral Tropism Switch and HIV-Mediated CD4 Depletion." Current HIV Research 17, no. 6: 388-396.
P-selectin glycoprotein ligand-1 (PSGL-1) is a dimeric, mucin-like, 120-kDa glycoprotein that binds to P-, E-, and L-selectins. PSGL-1 is primarily expressed on the surface of lymphoid and myeloid cells and is up-regulated during inflammation to mediate leukocyte tethering and rolling on the surface of endothelium for migration into inflamed tissues. Although it has been reported that PSGL-1 expression inhibits human immunodeficiency virus type 1 (HIV-1) replication, the mechanism of PSGL-1-mediated anti-HIV activity remains to be elucidated. Here, we report that PSGL-1 in virions blocks the infectivity of HIV-1 particles by preventing the binding of particles to target cells. This inhibitory activity is independent of the viral glycoprotein present on the virus particle; the binding of particles bearing the HIV-1 envelope glycoprotein, vesicular stomatitis virus G glycoprotein, or lacking a viral glycoprotein, is impaired by PSGL-1. Mapping studies show that the extracellular, N-terminal domain of PSGL-1 is necessary for its anti-HIV-1 activity, and the PSGL-1 cytoplasmic tail contributes to its inhibition. In addition, we demonstrate that the PSGL-1-related monomeric E-selectin-binding glycoprotein CD43 also effectively blocks HIV-1 infectivity. HIV-1 infection, or the expression of either Vpu or Nef, downregulates PSGL-1 from the cell surface; the expression of Vpu appears to be primarily responsible for enabling the virus to partially escape PSGL-1-mediated restriction. Finally, we show that PSGL-1 inhibits the infectivity of other viruses such as murine leukemia virus and influenza A virus. These findings demonstrate that PSGL-1 is a broad-spectrum antiviral host factor with a novel mechanism of action.
Yajing Fu; Sijia He; Abdul Waheed; Deemah Dabbagh; Zheng Zhou; Benjamin Trinité; Zhao Wang; Jieshi Yu; Dan Wang; Feng Li; David N Levy; Hong Shang; Eric O Freed; Yuntao Wu. PSGL-1 Restricts HIV-1 Infectivity by Blocking Virus Particle Attachment to Target Cells. Proceedings 2020, 50, 77 .
AMA StyleYajing Fu, Sijia He, Abdul Waheed, Deemah Dabbagh, Zheng Zhou, Benjamin Trinité, Zhao Wang, Jieshi Yu, Dan Wang, Feng Li, David N Levy, Hong Shang, Eric O Freed, Yuntao Wu. PSGL-1 Restricts HIV-1 Infectivity by Blocking Virus Particle Attachment to Target Cells. Proceedings. 2020; 50 (1):77.
Chicago/Turabian StyleYajing Fu; Sijia He; Abdul Waheed; Deemah Dabbagh; Zheng Zhou; Benjamin Trinité; Zhao Wang; Jieshi Yu; Dan Wang; Feng Li; David N Levy; Hong Shang; Eric O Freed; Yuntao Wu. 2020. "PSGL-1 Restricts HIV-1 Infectivity by Blocking Virus Particle Attachment to Target Cells." Proceedings 50, no. 1: 77.
A functional HIV cure requires immune reconstitution for lasting viremia control. A major immune dysfunction persisting in HIV infection is the impairment of T helper cell migration and homing to lymphoid tissues such as GALTs (gut-associated lymphoid tissues). ART (antiretroviral therapy) does not fully restore T cell motility for tissue repopulation. The molecular mechanism dictating this persistent T cell dysfunction is not understood. Cofilin is an actin-depolymerizing factor that regulates actin dynamics for T cell migration. Here, we demonstrate that blood CD4 T cells from HIV-infected patients (n = 193), with or without ART, exhibit significantly lower levels of cofilin phosphorylation (hyperactivation) than those from healthy controls (n = 100; ratio, 1.1:2.3; P < 0.001); cofilin hyperactivation is also associated with poor CD4 T cell recovery following ART. These results suggest an HIV-mediated systemic dysregulation of T cell motility that cannot be repaired solely by ART. We further demonstrate that stimulating blood CD4 T cells with an anti–human α4β7 integrin antibody can trigger signal transduction and modulate the cofilin pathway, partially restoring T cell motility in vitro. However, we also observed that severe T cell motility defect caused by high degrees of cofilin hyperactivation was not repairable by the anti-integrin antibody, demonstrating a mechanistic hindrance to restore immune functions in vivo. Our study suggests that cofilin is a key molecule that may need to be therapeutically targeted early for T cell tissue repopulation, immune reconstitution, and immune control of viremia.
Sijia He; Yajing Fu; Jia Guo; Mark Spear; Jiuling Yang; Benjamin Trinité; Chaolong Qin; Shuai Fu; Yongjun Jiang; Zining Zhang; Junjie Xu; Haibo Ding; David N. Levy; Wanjun Chen; Emanuel Petricoin; Lance A. Liotta; Hong Shang; Yuntao Wu. Cofilin hyperactivation in HIV infection and targeting the cofilin pathway using an anti-α4β7 integrin antibody. Science Advances 2019, 5, eaat7911 .
AMA StyleSijia He, Yajing Fu, Jia Guo, Mark Spear, Jiuling Yang, Benjamin Trinité, Chaolong Qin, Shuai Fu, Yongjun Jiang, Zining Zhang, Junjie Xu, Haibo Ding, David N. Levy, Wanjun Chen, Emanuel Petricoin, Lance A. Liotta, Hong Shang, Yuntao Wu. Cofilin hyperactivation in HIV infection and targeting the cofilin pathway using an anti-α4β7 integrin antibody. Science Advances. 2019; 5 (1):eaat7911.
Chicago/Turabian StyleSijia He; Yajing Fu; Jia Guo; Mark Spear; Jiuling Yang; Benjamin Trinité; Chaolong Qin; Shuai Fu; Yongjun Jiang; Zining Zhang; Junjie Xu; Haibo Ding; David N. Levy; Wanjun Chen; Emanuel Petricoin; Lance A. Liotta; Hong Shang; Yuntao Wu. 2019. "Cofilin hyperactivation in HIV infection and targeting the cofilin pathway using an anti-α4β7 integrin antibody." Science Advances 5, no. 1: eaat7911.
Events occurring during the initial phase of human immunodeficiency virus (HIV) infection are intriguing because of their dramatic impact on the subsequent course of the disease. In particular, the relationship between myeloid-derived suppressor cells (MDSCs) and HIV pathogenesis in primary infection remains unknown and the mechanism of MDSCs in HIV infection are incompletely defined. The frequency of MDSC expression in patients with primary HIV infection (PHI) and chronic HIV infection was measured, and the association with disease progression was studied. Programmed death-ligand 1 (PD-L1) and galectin-9 (Gal-9) expression on MDSCs was measured and in vitro blocking experiments were performed to study the role of PD-L1 in MDSCs' inhibition. We found increased levels of HLA-DR−/lowCD14−CD33+CD11b+ granulocytic(G)-MDSCs in PHI individuals compared with normal controls, which correlated with viral loads and was negatively related to CD4+ T-cell levels. When cocultured with purified G-MDSCs, both proliferation and interferon-γ secretion by T cell receptor (TCR)-stimulated CD8+ T cells from HIV-infected patients were significantly inhibited. We also demonstrated that PD-L1, but not Gal-9, expression on HLA-DR−/lowCD14−CD33+CD11b+ cells increased during HIV infection. The suppressive activity of G-MDSCs from HIV-infected patients was attenuated by PD-L1 blockade. We found a significant increase in G-MDSCs in PHI patients that was related to disease progression and PD-L1 was used by MDSCs to inhibit CD8+ T cells in HIV infection. Our data improve the understanding of HIV pathogenesis in PHI.
Zi-Ning Zhang; Nan Yi; Tong-Wei Zhang; Le-Le Zhang; Xian Wu; Mei Liu; Ya-Jing Fu; Si-Jia He; Yong-Jun Jiang; Hai-Bo Ding; Zhen-Xing Chu; Hong Shang. Myeloid-Derived Suppressor Cells Associated With Disease Progression in Primary HIV Infection: PD-L1 Blockade Attenuates Inhibition. JAIDS Journal of Acquired Immune Deficiency Syndromes 2017, 76, 200 -208.
AMA StyleZi-Ning Zhang, Nan Yi, Tong-Wei Zhang, Le-Le Zhang, Xian Wu, Mei Liu, Ya-Jing Fu, Si-Jia He, Yong-Jun Jiang, Hai-Bo Ding, Zhen-Xing Chu, Hong Shang. Myeloid-Derived Suppressor Cells Associated With Disease Progression in Primary HIV Infection: PD-L1 Blockade Attenuates Inhibition. JAIDS Journal of Acquired Immune Deficiency Syndromes. 2017; 76 (2):200-208.
Chicago/Turabian StyleZi-Ning Zhang; Nan Yi; Tong-Wei Zhang; Le-Le Zhang; Xian Wu; Mei Liu; Ya-Jing Fu; Si-Jia He; Yong-Jun Jiang; Hai-Bo Ding; Zhen-Xing Chu; Hong Shang. 2017. "Myeloid-Derived Suppressor Cells Associated With Disease Progression in Primary HIV Infection: PD-L1 Blockade Attenuates Inhibition." JAIDS Journal of Acquired Immune Deficiency Syndromes 76, no. 2: 200-208.
A dynamic actin cytoskeleton is necessary for viral entry, intracellular migration, and virion release. For HIV-1 infection, during entry, the virus triggers early actin activity by hijacking chemokine coreceptor signaling, which activates a host dependency factor, cofilin, and its kinase, the LIM domain kinase (LIMK). Although knockdown of human LIM domain kinase 1 (LIMK1) with short hairpin RNA (shRNA) inhibits HIV infection, no specific small-molecule inhibitor of LIMK has been available. Here, we describe the design and discovery of novel classes of small-molecule inhibitors of LIMK for inhibiting HIV infection. We identified R10015 as a lead compound that blocks LIMK activity by binding to the ATP-binding pocket. R10015 specifically blocks viral DNA synthesis, nuclear migration, and virion release. In addition, R10015 inhibits multiple viruses, including Zaire ebolavirus (EBOV), Rift Valley fever virus (RVFV), Venezuelan equine encephalitis virus (VEEV), and herpes simplex virus 1 (HSV-1), suggesting that LIMK inhibitors could be developed as a new class of broad-spectrum antiviral drugs. IMPORTANCE The actin cytoskeleton is a structure that gives the cell shape and the ability to migrate. Viruses frequently rely on actin dynamics for entry and intracellular migration. In cells, actin dynamics are regulated by kinases, such as the LIM domain kinase (LIMK), which regulates actin activity through phosphorylation of cofilin, an actin-depolymerizing factor. Recent studies have found that LIMK/cofilin are targeted by viruses such as HIV-1 for propelling viral intracellular migration. Although inhibiting LIMK1 expression blocks HIV-1 infection, no highly specific LIMK inhibitor is available. This study describes the design, medicinal synthesis, and discovery of small-molecule LIMK inhibitors for blocking HIV-1 and several other viruses and emphasizes the feasibility of developing LIMK inhibitors as broad-spectrum antiviral drugs.
Fei Yi; Jia Guo; Deemah Dabbagh; Mark Spear; Sijia He; Kylene Kehn-Hall; Jacque Fontenot; Yan Yin; Mathieu Bibian; Chul Min Park; Ke Zheng; Ha Jeung Park; Veronica Soloveva; Dima Gharaibeh; Cary Retterer; Rouzbeh Zamani; Margaret L. Pitt; John Naughton; Yongjun Jiang; Hong Shang; Ramin M. Hakami; Binhua Ling; John A. T. Young; Sina Bavari; Xuehua Xu; Yangbo Feng; Yuntao Wu. Discovery of Novel Small-Molecule Inhibitors of LIM Domain Kinase for Inhibiting HIV-1. Journal of Virology 2017, 91, e02418-16 .
AMA StyleFei Yi, Jia Guo, Deemah Dabbagh, Mark Spear, Sijia He, Kylene Kehn-Hall, Jacque Fontenot, Yan Yin, Mathieu Bibian, Chul Min Park, Ke Zheng, Ha Jeung Park, Veronica Soloveva, Dima Gharaibeh, Cary Retterer, Rouzbeh Zamani, Margaret L. Pitt, John Naughton, Yongjun Jiang, Hong Shang, Ramin M. Hakami, Binhua Ling, John A. T. Young, Sina Bavari, Xuehua Xu, Yangbo Feng, Yuntao Wu. Discovery of Novel Small-Molecule Inhibitors of LIM Domain Kinase for Inhibiting HIV-1. Journal of Virology. 2017; 91 (13):e02418-16.
Chicago/Turabian StyleFei Yi; Jia Guo; Deemah Dabbagh; Mark Spear; Sijia He; Kylene Kehn-Hall; Jacque Fontenot; Yan Yin; Mathieu Bibian; Chul Min Park; Ke Zheng; Ha Jeung Park; Veronica Soloveva; Dima Gharaibeh; Cary Retterer; Rouzbeh Zamani; Margaret L. Pitt; John Naughton; Yongjun Jiang; Hong Shang; Ramin M. Hakami; Binhua Ling; John A. T. Young; Sina Bavari; Xuehua Xu; Yangbo Feng; Yuntao Wu. 2017. "Discovery of Novel Small-Molecule Inhibitors of LIM Domain Kinase for Inhibiting HIV-1." Journal of Virology 91, no. 13: e02418-16.
Forkhead box O (FOXO)1, FOXO3, interferon regulatory factor (IRF)4, X-linked inhibitor of apoptosis protein (xIAP), and E74-like factor (ELF)4 have been described as important regulators of T cell functions and differentiation. However, whether these molecules are associated with HIV-1 disease progression is still unknown. In this study, we showed that the levels of FOXO3, IRF4, and xIAP mRNA in rapid progressors (RPs) were significantly higher than in HIV-negative healthy controls (HCs). Moreover, FOXO3 expression was positively correlated with HIV-1 viral load and CD4+ T cell activation. Remarkably, increased CD4+ and CD8+ T cell activation was apparent in RPs compared with typical progressors and HCs. In addition, a profile of higher apoptosis, more CD8+ TEM cells, and fewer CD4+ and CD8+ Naive T cells were observed in early HIV infection patients with low CD4+ T cell counts. Furthermore, in vitro, IRF4 and xIAP expression was enhanced in peripheral blood mononuclear cells from healthy people following T cell receptor stimulation. T cell activation was decreased by treatment with siRNA inhibiting FOXO3, IRF4, and xIAP. Our results show that significantly increased levels of FOXO3, IRF4, and xIAP mRNA in Chinese HIV-1-infected patients were related to T cell immune activation, implicating them as potential targets for developing new therapeutic avenues to slow down HIV-1 disease progression.
Xiaowei Zhang; Zining Zhang; Sijia He; Yajing Fu; Yanhong Chen; Nan Yi; Yongjun Jiang; Wenqing Geng; Hong Shang. FOXO3, IRF4, and xIAP Are Correlated with Immune Activation in HIV-1-Infected Men Who Have Sex with Men During Early HIV Infection. AIDS Research and Human Retroviruses 2017, 33, 172 -180.
AMA StyleXiaowei Zhang, Zining Zhang, Sijia He, Yajing Fu, Yanhong Chen, Nan Yi, Yongjun Jiang, Wenqing Geng, Hong Shang. FOXO3, IRF4, and xIAP Are Correlated with Immune Activation in HIV-1-Infected Men Who Have Sex with Men During Early HIV Infection. AIDS Research and Human Retroviruses. 2017; 33 (2):172-180.
Chicago/Turabian StyleXiaowei Zhang; Zining Zhang; Sijia He; Yajing Fu; Yanhong Chen; Nan Yi; Yongjun Jiang; Wenqing Geng; Hong Shang. 2017. "FOXO3, IRF4, and xIAP Are Correlated with Immune Activation in HIV-1-Infected Men Who Have Sex with Men During Early HIV Infection." AIDS Research and Human Retroviruses 33, no. 2: 172-180.
HIV-1 causes chronic infection characterized by the depletion of CD4+ T lymphocytes and the development of AIDS. Current antiretroviral drugs inhibit viral spread, but they do not lead to a full immune recovery. Hematopoietic stem cells (HSCs) and multipotent hematopoietic progenitor cells (HPCs) give rise to all blood and immune cells, and in HIV infection, hematological abnormalities frequently occur in patients. Here, we used bone marrow samples from HIV-1–infected people to study the relationship between the proliferation ability of HSCs/HPCs and peripheral CD4+ T lymphocytes. Three indexes were used to reflect the proliferation ability of HSCs and HPCs: (1) colony-forming units of bone marrow mononuclear cells (BMMCs), (2) amplification of CD34+ cells purified from bone marrow mononuclear cells, (3) expression of HOXB4 and HOXA9 in CD34+ cells. We observed a direct correlation between peripheral number of CD4+ T lymphocytes and the HSCs/HPCs proliferation ability in our study. We also compared HIV-infected patients with or without antiretroviral therapy (ART). Our results demonstrated that after antiretroviral therapy, CD4+ T-cell recovery and HPCs proliferation ability are correlated. Our findings have implications in understanding whether bone marrow-derived HPCs can supplement for the loss of CD4+ T lymphocytes during HIV-1 infection.
Xiaolin Guo; Sijia He; Xiaoyi Lv; Haibo Ding; Sha Li; Jing Kang; Jing Liu; Chaolong Qin; Wenqing Geng; Yongjun Jiang; Hong Shang. The Role of HIV-1 in Affecting the Proliferation Ability of HPCs Derived From BM. JAIDS Journal of Acquired Immune Deficiency Syndromes 2016, 71, 467 -473.
AMA StyleXiaolin Guo, Sijia He, Xiaoyi Lv, Haibo Ding, Sha Li, Jing Kang, Jing Liu, Chaolong Qin, Wenqing Geng, Yongjun Jiang, Hong Shang. The Role of HIV-1 in Affecting the Proliferation Ability of HPCs Derived From BM. JAIDS Journal of Acquired Immune Deficiency Syndromes. 2016; 71 (5):467-473.
Chicago/Turabian StyleXiaolin Guo; Sijia He; Xiaoyi Lv; Haibo Ding; Sha Li; Jing Kang; Jing Liu; Chaolong Qin; Wenqing Geng; Yongjun Jiang; Hong Shang. 2016. "The Role of HIV-1 in Affecting the Proliferation Ability of HPCs Derived From BM." JAIDS Journal of Acquired Immune Deficiency Syndromes 71, no. 5: 467-473.
In HIV disease course, the decline of peripheral CD4 T-cell count correlates with rapid disease progression. The supply of peripheral naive T cells by the thymus requires precursor T-cell proliferation within the thymus. In the setting of HIV-1 infection, when both naive and memory T cells are progressively depleted, the contribution of thymic dysfunction in CD4 depletion needs to be studied. Previous research has shown that thymic function may also be impaired in HIV-1 infection. However, it is inconclusive regarding whether this impairment occurred at the early time or during the chronic phase. In addition, the relationship between thymic dysfunction and disease progression remains unknown. In this study, we examined the thymic function in 65 HIV-infected individuals. Among them, 17 were in acute phase, 15 were in early chronic phase, 15 were in chronic phase with no ART (antiretroviral therapy), and 18 were on ART. We also included 11 uninfected individuals as controls. We measured the peripheral blood levels of T-cell receptor rearrangement excision circles and PTK7 and CD31 expressions for the frequency of circulating recent thymic emigrants. We observed that the 2 indicators of thymic function, sj/β-TREC and PTK7, seemed to be lower in the chronic infection group than those in the acute and early chronic groups. Both indicators returned to the normal level after ART. However, after 1-year follow-up of patients with early HIV-1 infection, rapid progressors (n = 4) had lower PTK7 and CD31 expressions than chronic progressors (n = 6).
Sijia He; Zining Zhang; Yajing Fu; Chaolong Qin; Sha Li; Xiaoxu Han; Junjie Xu; Jing Liu; Yongjun Jiang; Hong Shang. Thymic Function Is Most Severely Impaired in Chronic HIV-1 Infection, but Individuals With Faster Disease Progression During Early HIV-1 Infection Expressed Lower Levels of RTEs. JAIDS Journal of Acquired Immune Deficiency Syndromes 2015, 70, 472 -478.
AMA StyleSijia He, Zining Zhang, Yajing Fu, Chaolong Qin, Sha Li, Xiaoxu Han, Junjie Xu, Jing Liu, Yongjun Jiang, Hong Shang. Thymic Function Is Most Severely Impaired in Chronic HIV-1 Infection, but Individuals With Faster Disease Progression During Early HIV-1 Infection Expressed Lower Levels of RTEs. JAIDS Journal of Acquired Immune Deficiency Syndromes. 2015; 70 (5):472-478.
Chicago/Turabian StyleSijia He; Zining Zhang; Yajing Fu; Chaolong Qin; Sha Li; Xiaoxu Han; Junjie Xu; Jing Liu; Yongjun Jiang; Hong Shang. 2015. "Thymic Function Is Most Severely Impaired in Chronic HIV-1 Infection, but Individuals With Faster Disease Progression During Early HIV-1 Infection Expressed Lower Levels of RTEs." JAIDS Journal of Acquired Immune Deficiency Syndromes 70, no. 5: 472-478.
The human immunodeficiency virus type 1 (HIV-1) initiates receptor signaling and early actin dynamics during viral entry. This process is required for viral infection of primary targets such as resting CD4 T cells. WAVE2 is a component of a multiprotein complex linking receptor signaling to dynamic remodeling of the actin cytoskeleton. WAVE2 directly activates Arp2/3, leading to actin nucleation and filament branching. Although several bacterial and viral pathogens target Arp2/3 for intracellular mobility, it remains unknown whether HIV-1 actively modulates the Arp2/3 complex through virus-mediated receptor signal transduction. Here we report that HIV-1 triggers WAVE2 phosphorylation at serine 351 through gp120 binding to the chemokine coreceptor CXCR4 or CCR5 during entry. This phosphorylation event involves both Gαi-dependent and -independent pathways, and is conserved both in X4 and R5 viral infection of resting CD4 T cells and primary macrophages. We further demonstrate that inhibition of WAVE2-mediated Arp2/3 activity through stable shRNA knockdown of Arp3 dramatically diminished HIV-1 infection of CD4 T cells, preventing viral nuclear migration. Inhibition of Arp2/3 through a specific inhibitor, CK548, also drastically inhibited HIV-1 nuclear migration and infection of CD4 T cells. Our results suggest that Arp2/3 and the upstream regulator, WAVE2, are essential co-factors hijacked by HIV for intracellular migration, and may serve as novel targets to prevent HIV transmission.
Mark Spear; Jia Guo; Amy Turner; Dongyang Yu; Weifeng Wang; Beatrix Meltzer; Sijia He; Xiaohua Hu; Hong Shang; Jeffrey Kuhn; Yuntao Wu. HIV-1 Triggers WAVE2 Phosphorylation in Primary CD4 T Cells and Macrophages, Mediating Arp2/3-dependent Nuclear Migration. Journal of Biological Chemistry 2014, 289, 6949 -6959.
AMA StyleMark Spear, Jia Guo, Amy Turner, Dongyang Yu, Weifeng Wang, Beatrix Meltzer, Sijia He, Xiaohua Hu, Hong Shang, Jeffrey Kuhn, Yuntao Wu. HIV-1 Triggers WAVE2 Phosphorylation in Primary CD4 T Cells and Macrophages, Mediating Arp2/3-dependent Nuclear Migration. Journal of Biological Chemistry. 2014; 289 (10):6949-6959.
Chicago/Turabian StyleMark Spear; Jia Guo; Amy Turner; Dongyang Yu; Weifeng Wang; Beatrix Meltzer; Sijia He; Xiaohua Hu; Hong Shang; Jeffrey Kuhn; Yuntao Wu. 2014. "HIV-1 Triggers WAVE2 Phosphorylation in Primary CD4 T Cells and Macrophages, Mediating Arp2/3-dependent Nuclear Migration." Journal of Biological Chemistry 289, no. 10: 6949-6959.