615 results on '"YONG-TANG ZHENG"'
Search Results
2. Increased cAMP-PKA signaling pathway activation is involved in up-regulation of CTLA-4 expression in CD4+ T cells in acute SIVmac239-infected Chinese rhesus macaques
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Ren-Rong Tian, Ben-Bo Liu, Ming-Liang Zhao, Yu-Jun Cai, and Yong-Tang Zheng
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HIV ,CTLA-4 ,cAMP-PKA signaling pathway ,Non-human primate models ,Microbiology ,QR1-502 ,Infectious and parasitic diseases ,RC109-216 - Abstract
Human immunodeficiency virus-1 (HIV-1) infection can cause chronic activation, exhaustion, and anergy of the immune system. Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is an immune checkpoint molecule, which plays an important role in immune homeostasis and disease. CTLA-4 expression is elevated in HIV-1-infected patients and is associated with disease progression. However, the mechanism controlling expression of CTLA-4 in HIV-1 infection is poorly characterized. In this study, we used a SIV-infected Chinese rhesus macaque (ChRM) model to explore CTLA-4 expression in SIV infection. Results showed that SIV infection significantly increased CTLA-4 expression in all T cell subsets, especially central memory T cells. CTLA-4+CD4+ T cell frequency was significantly associated with disease progression markers. Activation of the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) signaling pathway regulated CTLA-4 expression in CD4+T cells, as confirmed by stimulation with dibutyryl cyclic adenosine monophosphate, forskolin, and 3-isobutyl-1-methylxanthine, and inhibition with H-89 ex vivo. Simultaneously, cAMP concentration in PBMCs and PKA activity in both PBMCs and CD4+ T cells were increased in acute SIV-infected ChRMs, accompanied by an increase in adenylate cyclase 6 expression and a decrease in cAMP-phosphodiesterase 3A (PDE3A), PDE4B, and PDE5A expression in PBMCs. In addition, selective inhibition of PDE4B and PDE5A activity enhanced CTLA-4 expression in CD4+ T cells. These results suggest that SIV infection alters cAMP metabolism and increases cAMP-PKA signaling pathway activation, which up-regulates the expression of CTLA-4 in acute SIVmac239-infected ChRMs. Thus, regulation of the cAMP-PKA signaling pathway may be a potential strategy for the restoration of T cell function and therapy for AIDS.
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- 2024
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3. Transcriptional regulation of SARS-CoV-2 receptor ACE2 by SP1
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Hui Han, Rong-Hua Luo, Xin-Yan Long, Li-Qiong Wang, Qian Zhu, Xin-Yue Tang, Rui Zhu, Yi-Cheng Ma, Yong-Tang Zheng, and Cheng-Gang Zou
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SARS-CoV-2 ,ACE2 ,Sp1 ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Angiotensin-converting enzyme 2 (ACE2) is a major cell entry receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The induction of ACE2 expression may serve as a strategy by SARS-CoV-2 to facilitate its propagation. However, the regulatory mechanisms of ACE2 expression after viral infection remain largely unknown. Using 45 different luciferase reporters, the transcription factors SP1 and HNF4α were found to positively and negatively regulate ACE2 expression, respectively, at the transcriptional level in human lung epithelial cells (HPAEpiCs). SARS-CoV-2 infection increased the transcriptional activity of SP1 while inhibiting that of HNF4α. The PI3K/AKT signaling pathway, activated by SARS-CoV-2 infection, served as a crucial regulatory node, inducing ACE2 expression by enhancing SP1 phosphorylation—a marker of its activity—and reducing the nuclear localization of HNF4α. However, colchicine treatment inhibited the PI3K/AKT signaling pathway, thereby suppressing ACE2 expression. In Syrian hamsters (Mesocricetus auratus) infected with SARS-CoV-2, inhibition of SP1 by either mithramycin A or colchicine resulted in reduced viral replication and tissue injury. In summary, our study uncovers a novel function of SP1 in the regulation of ACE2 expression and identifies SP1 as a potential target to reduce SARS-CoV-2 infection.
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- 2024
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4. HR121 targeting HR2 domain in S2 subunit of spike protein can serve as a broad-spectrum SARS-CoV-2 inhibitor via intranasal administration
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Ying Lu, Fan Shen, Wen-Qiang He, An-Qi Li, Ming-Hua Li, Xiao-Li Feng, Yong-Tang Zheng, and Wei Pang
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SARS-CoV-2 ,S2 subunit ,Heptad repeat 2 ,HR121 ,Fusion inhibitor ,Intranasal administration ,Therapeutics. Pharmacology ,RM1-950 - Abstract
The continuously emerging SARS-CoV-2 variants pose a great challenge to the efficacy of current drugs, this necessitates the development of broad-spectrum antiviral drugs. In the previous study, we designed a recombinant protein, heptad repeat (HR) 121, as a variant-proof vaccine. Here, we found it can act as a fusion inhibitor and demonstrated broadly neutralizing activities against SARS-CoV-2 and its main variants. Structure analysis suggested that HR121 targets the HR2 domain in SARS-CoV-2 spike (S) 2 subunit to block virus-cell fusion. Functional experiments demonstrated that HR121 can bind HR2 at serological-pH and endosomal-pH, highlighting its inhibition capacity when SARS-CoV-2 enters via either cellular membrane fusion or endosomal route. Importantly, HR121 can effectively inhibit SARS-CoV-2 and Omicron variant pseudoviruses entering the cells, as well as block authentic SARS-CoV-2 and Omicron BA.2 replications in human pulmonary alveolar epithelial cells. After intranasal administration to Syrian golden hamsters, it can protect hamsters from SARS-CoV-2 and Omicron BA.2 infection. Together, our results suggest that HR121 is a potent drug candidate with broadly neutralizing activities against SARS-CoV-2 and its variants.
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- 2023
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5. Temporal trends and projections of gynecological cancers in China, 2007–2030
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Rufei Duan, Hongping Zhang, Jing Yu, Sisi Deng, Haijun Yang, Yong-Tang Zheng, Yunchao Huang, Fanghui Zhao, and Hongying Yang
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Gynecological cancer ,Temporal trend ,AAPC ,Projection ,China ,Gynecology and obstetrics ,RG1-991 ,Public aspects of medicine ,RA1-1270 - Abstract
Abstract Background Gynecological cancer will become a more important public health problem in future years but limited evidence on gynecological cancer burden in China. Methods We extracted age-specific rate of cancer cases and deaths during 2007–2016 from the Chinese Cancer Registry Annual Report, and estimated age-specific population size using the data released by National Bureau of Statistics of China. Cancer burden were calculated by multiplying the rates with the population size. Temporal trends of the cancer cases, incidence, deaths, and mortality during 2007–2016 were calculated by JoinPoint Regression Program, and from 2017 to 2030 were projected by grey prediction model GM (1,1). Results In China, total gynecological cancer cases increased from 177,839 to 241,800, with the average annual percentage change of 3.5% (95% CI: 2.7–4.3%) during 2007–2016. Cervical, uterine, ovarian, vulva, and other gynecological cancer cases increased by 4.1% (95% CI: 3.3–4.9%), 3.3% (95% CI: 2.6–4.1%), 2.4% (95% CI: 1.4–3.5%), 4.4% (95% CI: 2.5–6.4%), and 3.6% (95% CI: 1.4–5.9%) respectively. From 2017 to 2030, projected gynecological cancer cases are changing from 246,581 to 408,314. Cervical, vulva and vaginal cancers showed evident upward trend, while uterine and ovarian cancer cases are slightly increasing. The increases for age-standardized incidence rates were similar with that of cancer cases. Temporal trends of cancer deaths and mortality were similar with that of cancer cases and incidence during 2007–2030, except that uterine cancer deaths and mortality were declined. Conclusions With the aging of population and other increased risk factors, the burden of gynecological cancers in China is likely to be grew rapidly in the future, comprehensive gynecological cancer control should be concerned.
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- 2023
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6. Immune resilience despite inflammatory stress promotes longevity and favorable health outcomes including resistance to infection
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Sunil K. Ahuja, Muthu Saravanan Manoharan, Grace C. Lee, Lyle R. McKinnon, Justin A. Meunier, Maristella Steri, Nathan Harper, Edoardo Fiorillo, Alisha M. Smith, Marcos I. Restrepo, Anne P. Branum, Matthew J. Bottomley, Valeria Orrù, Fabio Jimenez, Andrew Carrillo, Lavanya Pandranki, Caitlyn A. Winter, Lauryn A. Winter, Alvaro A. Gaitan, Alvaro G. Moreira, Elizabeth A. Walter, Guido Silvestri, Christopher L. King, Yong-Tang Zheng, Hong-Yi Zheng, Joshua Kimani, T. Blake Ball, Francis A. Plummer, Keith R. Fowke, Paul N. Harden, Kathryn J. Wood, Martin T. Ferris, Jennifer M. Lund, Mark T. Heise, Nigel Garrett, Kristen R. Canady, Salim S. Abdool Karim, Susan J. Little, Sara Gianella, Davey M. Smith, Scott Letendre, Douglas D. Richman, Francesco Cucca, Hanh Trinh, Sandra Sanchez-Reilly, Joan M. Hecht, Jose A. Cadena Zuluaga, Antonio Anzueto, Jacqueline A. Pugh, South Texas Veterans Health Care System COVID-19 team, Brian K. Agan, Robert Root-Bernstein, Robert A. Clark, Jason F. Okulicz, and Weijing He
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Science - Abstract
Abstract Some people remain healthier throughout life than others but the underlying reasons are poorly understood. Here we hypothesize this advantage is attributable in part to optimal immune resilience (IR), defined as the capacity to preserve and/or rapidly restore immune functions that promote disease resistance (immunocompetence) and control inflammation in infectious diseases as well as other causes of inflammatory stress. We gauge IR levels with two distinct peripheral blood metrics that quantify the balance between (i) CD8+ and CD4+ T-cell levels and (ii) gene expression signatures tracking longevity-associated immunocompetence and mortality-associated inflammation. Profiles of IR metrics in ~48,500 individuals collectively indicate that some persons resist degradation of IR both during aging and when challenged with varied inflammatory stressors. With this resistance, preservation of optimal IR tracked (i) a lower risk of HIV acquisition, AIDS development, symptomatic influenza infection, and recurrent skin cancer; (ii) survival during COVID-19 and sepsis; and (iii) longevity. IR degradation is potentially reversible by decreasing inflammatory stress. Overall, we show that optimal IR is a trait observed across the age spectrum, more common in females, and aligned with a specific immunocompetence-inflammation balance linked to favorable immunity-dependent health outcomes. IR metrics and mechanisms have utility both as biomarkers for measuring immune health and for improving health outcomes.
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- 2023
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7. TRIM5α recruits HDAC1 to p50 and Sp1 and promotes H3K9 deacetylation at the HIV-1 LTR
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Xiang-Hong Ran, Jia-Wu Zhu, Run-Ze Ni, Yong-Tang Zheng, Ya-Yun Chen, Wei-Hua Zheng, and Dan Mu
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Science - Abstract
Abstract Tripartite motif-containing protein 5α (TRIM5α) is generally known to block the postentry events of HIV-1. Here, we report an uncharacterized role for TRIM5α in the maintenance of viral latency. Knockdown of TRIM5α potentiates the transcription of HIV-1 in multiple latency models, which is reversed by shRNA-resistant TRIM5α. TRIM5α suppresses TNFα-activated HIV-1 LTR-driven as well as NF-κB- and Sp1-driven gene expression, with the RING and B-box 2 domains being the essential determinants. Mechanistically, TRIM5α binds to and enhances the recruitment of histone deacetylase 1 (HDAC1) to NF-κB p50 and Sp1. ChIP‒qPCR analyses further reveal that the association of TRIM5α with HIV-1 LTR induces HDAC1 recruitment and local H3K9 deacetylation. Conserved suppression effects of TRIM5α orthologs from multiple species on both HIV-1 and endo-retroelement HERV-K LTR activities have also been demonstrated. These findings provide new insights into the molecular mechanisms by which proviral latency is initially established and activatable proviruses are resilenced by histone deacetylase recruitment.
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- 2023
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8. Novel Circovirus in Blood from Intravenous Drug Users, Yunnan, China
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Yanpeng Li, Peng Zhang, Mei Ye, Ren-Rong Tian, Na Li, Le Cao, Yingying Ma, Feng-Liang Liu, Yong-Tang Zheng, and Chiyu Zhang
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circovirus ,IDU ,intravenous drug users ,viruses ,viral metagenomics ,emerging virus ,Medicine ,Infectious and parasitic diseases ,RC109-216 - Abstract
We identified a novel circovirus (human-associated circovirus 2 [HuCV2]) from the blood of 2 intravenous drug users in China who were infected with HIV-1, hepatitis C virus, or both. HuCV2 is most closely related to porcine circovirus 3. Our findings underscore the risk for HuCV2 and other emerging viruses among this population.
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- 2023
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9. Single-cell RNA sequencing reveals the fragility of male spermatogenic cells to Zika virus-induced complement activation
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Wei Yang, Li-Bo Liu, Feng-Liang Liu, Yan-Hua Wu, Zi-Da Zhen, Dong-Ying Fan, Zi-Yang Sheng, Zheng-Ran Song, Jia-Tong Chang, Yong-Tang Zheng, Jing An, and Pei-Gang Wang
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Science - Abstract
Abstract Zika virus (ZIKV) is a potential threat to male reproductive health but the mechanisms underlying its influence on testes during ZIKV infection remain obscure. To address this question, we perform single-cell RNA sequencing using testes from ZIKV-infected mice. The results reveal the fragility of spermatogenic cells, especially spermatogonia, to ZIKV infection and show that the genes of the complement system are significantly upregulated mainly in infiltrated S100A4 + monocytes/macrophages. Complement activation and its contribution to testicular damage are validated by ELISA, RT‒qPCR and IFA and further verify in ZIKV-infected northern pigtailed macaques by RNA genome sequencing and IFA, suggesting that this might be the common response to ZIKV infection in primates. On this basis, we test the complement inhibitor C1INH and S100A4 inhibitors sulindac and niclosamide for their effects on testis protection. C1INH alleviates the pathological change in the testis but deteriorates ZIKV infection in general. In contrast, niclosamide effectively reduces S100A4 + monocyte/macrophage infiltration, inhibits complement activation, alleviates testicular damage, and rescues the fertility of male mice from ZIKV infection. This discovery therefore encourages male reproductive health protection during the next ZIKV epidemic.
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- 2023
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10. Preventive and therapeutic benefits of nelfinavir in rhesus macaques and human beings infected with SARS-CoV-2
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Zhijian Xu, Danrong Shi, Jian-Bao Han, Yun Ling, Xiangrui Jiang, Xiangyun Lu, Chuan Li, Likun Gong, Guangbo Ge, Yani Zhang, Yi Zang, Tian-Zhang Song, Xiao-Li Feng, Ren-Rong Tian, Jia Ji, Miaojin Zhu, Nanping Wu, Chunhui Wu, Zhen Wang, Yechun Xu, Cheng Peng, Min Zheng, Junling Yang, Feifei Du, Junliang Wu, Peipei Wang, Jingshan Shen, Jianliang Zhang, Yong-Tang Zheng, Hangping Yao, and Weiliang Zhu
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Medicine ,Biology (General) ,QH301-705.5 - Abstract
Abstract Effective drugs with broad spectrum safety profile to all people are highly expected to combat COVID-19 caused by SARS-CoV-2. Here we report that nelfinavir, an FDA approved drug for the treatment of HIV infection, is effective against SARS-CoV-2 and COVID-19. Preincubation of nelfinavir could inhibit the activity of the main protease of the SARS-CoV-2 (IC50 = 8.26 μM), while its antiviral activity in Vero E6 cells against a clinical isolate of SARS-CoV-2 was determined to be 2.93 μM (EC50). In comparison with vehicle-treated animals, rhesus macaque prophylactically treated with nelfinavir had significantly lower temperature and significantly reduced virus loads in the nasal and anal swabs of the animals. At necropsy, nelfinavir-treated animals had a significant reduction of the viral replication in the lungs by nearly three orders of magnitude. A prospective clinic study with 37 enrolled treatment-naive patients at Shanghai Public Health Clinical Center, which were randomized (1:1) to nelfinavir and control groups, showed that the nelfinavir treatment could shorten the duration of viral shedding by 5.5 days (9.0 vs. 14.5 days, P = 0.055) and the duration of fever time by 3.8 days (2.8 vs. 6.6 days, P = 0.014) in mild/moderate COVID-19 patients. The antiviral efficiency and clinical benefits in rhesus macaque model and in COVID-19 patients, together with its well-established good safety profile in almost all ages and during pregnancy, indicated that nelfinavir is a highly promising medication with the potential of preventative effect for the treatment of COVID-19.
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- 2023
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11. Extracellular vesicles mediate antibody-resistant transmission of SARS-CoV-2
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Bingqing Xia, Xiaoyan Pan, Rong-Hua Luo, Xurui Shen, Shuangqu Li, Yi Wang, Xiaoli Zuo, Yan Wu, Yingqi Guo, Gengfu Xiao, Qiguang Li, Xin-Yan Long, Xiao-Yan He, Hong-Yi Zheng, Ying Lu, Wei Pang, Yong-Tang Zheng, Jia Li, Lei-Ke Zhang, and Zhaobing Gao
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Cytology ,QH573-671 - Abstract
Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic. Antibody resistance dampens neutralizing antibody therapy and threatens current global Coronavirus (COVID-19) vaccine campaigns. In addition to the emergence of resistant SARS-CoV-2 variants, little is known about how SARS-CoV-2 evades antibodies. Here, we report a novel mechanism of extracellular vesicle (EV)-mediated cell-to-cell transmission of SARS-CoV-2, which facilitates SARS-CoV-2 to escape from neutralizing antibodies. These EVs, initially observed in SARS-CoV-2 envelope protein-expressing cells, are secreted by various SARS-CoV-2-infected cells, including Vero E6, Calu-3, and HPAEpiC cells, undergoing infection-induced pyroptosis. Various SARS-CoV-2-infected cells produce similar EVs characterized by extra-large sizes (1.6–9.5 μm in diameter, average diameter > 4.2 μm) much larger than previously reported virus-generated vesicles. Transmission electron microscopy analysis and plaque assay reveal that these SARS-CoV-2-induced EVs contain large amounts of live virus particles. In particular, the vesicle-cloaked SARS-CoV-2 virus is resistant to neutralizing antibodies and able to reinfect naïve cells independent of the reported receptors and cofactors. Consistently, the constructed 3D images show that intact EVs could be taken up by recipient cells directly, supporting vesicle-mediated cell-to-cell transmission of SARS-CoV-2. Our findings reveal a novel mechanism of receptor-independent SARS-CoV-2 infection via cell-to-cell transmission, provide new insights into antibody resistance of SARS-CoV-2 and suggest potential targets for future antiviral therapeutics.
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- 2023
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12. A Review on The Pathogenesis of Cardiovascular Disease of Flaviviridea Viruses Infection
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Tie-Hua Yang, Wen-Cong Gao, Xin Ma, Qian Liu, Pan-Pan Pang, Yong-Tang Zheng, Yinnong Jia, and Chang-Bo Zheng
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Flaviviridae viruses ,Flavivirus ,Hepacivirus ,cardiovascular disease ,Microbiology ,QR1-502 - Abstract
Members of the Flaviviridae family, encompassing the Flavivirus and Hepacivirus genera, are implicated in a spectrum of severe human pathologies. These diseases span a diverse spectrum, including hepatitis, vascular shock syndrome, encephalitis, acute flaccid paralysis, and adverse fetal outcomes, such as congenital heart defects and increased mortality rates. Notably, infections by Flaviviridae viruses have been associated with substantial cardiovascular compromise, yet the exploration into the attendant cardiovascular sequelae and underlying mechanisms remains relatively underexplored. This review aims to explore the epidemiology of Flaviviridae virus infections and synthesize their cardiovascular morbidities. Leveraging current research trajectories and our investigative contributions, we aspire to construct a cogent theoretical framework elucidating the pathogenesis of Flaviviridae-induced cardiovascular injury and illuminate prospective therapeutic avenues.
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- 2024
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13. Severe fever with thrombocytopenia syndrome virus induces platelet activation and apoptosis via a reactive oxygen species-dependent pathway
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Yi-Hui Li, Xue-Hui Wang, Wen-Wu Huang, Ren-Rong Tian, Wei Pang, and Yong-Tang Zheng
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SFTSV ,Thrombocytopenia ,Platelet activation ,Platelet apoptosis ,Antioxidants ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne infectious disease caused by the SFTS virus (SFTSV) and with a high fatality rate. Thrombocytopenia is a major clinical manifestation observed in SFTS patients, but the underlying mechanism remains largely unclear. Here, we explored the effects of SFTSV infection on platelet function in vivo in severely infected SFTSV IFNar−/− mice and on mouse and human platelet function in vitro. Results showed that SFTSV-induced platelet clearance acceleration may be the main reason for thrombocytopenia. SFTSV-potentiated platelet activation and apoptosis were also observed in infected mice. Further investigation showed that SFTSV infection induced platelet reactive oxygen species (ROS) production and mitochondrial dysfunction. In vitro experiments revealed that administration of SFTSV or SFTSV glycoprotein (Gn) increased activation, apoptosis, ROS production, and mitochondrial dysfunction in separated mouse platelets, which could be effectively ameliorated by the application of antioxidants (NAC (N-acetyl-l-cysteine), SKQ1 (10-(6′-plastoquinonyl) decyltriphenylphosphonium) and resveratrol). In vivo experiments showed that the antioxidants partially rescued SFTSV infection-induced thrombocytopenia by improving excessive ROS production and mitochondrial dysfunction and down-regulating platelet apoptosis and activation. Furthermore, while SFTSV and Gn directly potentiated human platelet activation, it was completely abolished by antioxidants. This study revealed that SFTSV and Gn can directly trigger platelet activation and apoptosis in an ROS-MAPK-dependent manner, which may contribute to thrombocytopenia and hemorrhage during infection, but can be abolished by antioxidants.
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- 2023
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14. Identification of two novel HIV-1 circulating recombinant forms of CRF111_01C and CRF116_0108 in southwestern Yunnan, China
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Mei Ye, Xin Chen, Lin Duo, Jin Ma, Le Cao, Chiyu Zhang, and Yong-Tang Zheng
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human immunodeficiency virus type 1 ,heterosexual contacts ,circulating recombinant forms ,china ,yunnan ,Infectious and parasitic diseases ,RC109-216 - Abstract
Yunnan, the region hardest hit by HIV/AIDS in China, is also an area with the most abundant HIV-1 genetic diversity. A large number of novel HIV-1 circulating recombinant forms (CRFs) and unique recombinants were identified among injection drug users in Yunnan; however, few were found among sexual contacts. Here, we obtained 15 near full-length genome sequences (NFLGs) from HIV-1 seropositive heterosexual contacts in Yunnan who received antiretroviral therapy during the period from 2014 to 2016. Phylogenetic analysis showed that six NFLGs belonged to CRF01_AE (n = 3) and CRF106_cpx (n = 3), and the other nine sequences were novel inter-subtype recombinants. Of the recombinants, two novel CRFs (CRF111_01 C (n = 4) and CRF116_0108 (n = 4)) and one CRF106_cpx variant (n = 1) were identified. CRF111_01 C had a CRF01_AE backbone with seven subtype C fragments inserted into the gag, pol, vif, env, nef and 3ʹLTR regions. CRF116_0108 had a CRF08_BC backbone with a CRF01_AE fragment inserted into the pol, tat, rev, vif, vpr, vpu and env regions. Phylogeographic analyses estimated that CRF111_01 C and CRF116_0108 originated approximately 1995.7–1998.6 and 1991.7–1993.7, respectively. These identifications of two novel HIV-1 CRFs highlighted the importance of continuous surveillance in heterosexual contacts and other high-risk groups in this region and the surrounding regions.
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- 2022
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15. A tandem-repeat dimeric RBD protein-based covid-19 vaccine zf2001 protects mice and nonhuman primates
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Yaling An, Shihua Li, Xiyue Jin, Jian-bao Han, Kun Xu, Senyu Xu, Yuxuan Han, Chuanyu Liu, Tianyi Zheng, Mei Liu, Mi Yang, Tian-Zhang Song, Baoying Huang, Li Zhao, Wen Wang, Ruhan A, Yingjie Cheng, Changwei Wu, Enqi Huang, Shilong Yang, Gary Wong, Yuhai Bi, Changwen Ke, Wenjie Tan, Jinghua Yan, Yong-Tang Zheng, Lianpan Dai, and George F. Gao
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Covid-19 ,subunit protein vaccine ,zf2001 ,antibody ,immune response ,Infectious and parasitic diseases ,RC109-216 ,Microbiology ,QR1-502 - Abstract
Safe, efficacious, and deployable vaccines are urgently needed to control COVID-19 in the large-scale vaccination campaigns. We report here the preclinical studies of an approved protein subunit vaccine against COVID-19, ZF2001, which contains tandem-repeat dimeric receptor-binding domain (RBD) protein with alum-based adjuvant. We assessed vaccine immunogenicity and efficacy in both mice and non-human primates (NHPs). ZF2001 induced high levels of RBD-binding and SARS-CoV-2 neutralizing antibody in both mice and non-human primates, and elicited balanced TH1/TH2 cellular responses in NHPs. Two doses of ZF2001 protected Ad-hACE2-transduced mice against SARS-CoV-2 infection, as detected by reduced viral RNA and relieved lung injuries. In NHPs, vaccination of either 25 μg or 50 μg ZF2001 prevented infection with SARS-CoV-2 in lung, trachea, and bronchi, with milder lung lesions. No evidence of disease enhancement was observed in both animal models. ZF2001 has been approved for emergency use in China, Uzbekistan, Indonesia, and Columbia. The high safety, immunogenicity, and protection efficacy in both mice and NHPs found in this preclinical study was consistent with the results in human clinical trials.
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- 2022
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16. Retrospective study of the immunogenicity and safety of the CoronaVac SARS-CoV-2 vaccine in people with underlying medical conditions
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Chunmei Li, Hanfang Bi, Zhenwang Fu, Ao Li, Na Wan, Jun Hu, Fan Yang, Tai-Cheng Zhou, Yupeng Liang, Wei Su, Tianpei Shi, Mei Yang, Rong Wang, Wanting Qin, Xuanjing Yu, Hong-Yi Zheng, Zumi Zhou, Yong-Tang Zheng, Jia Wei, Gang Zeng, Zijie Zhang, and the Precise-CoVaccine study group
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Medicine - Abstract
Li et al. evaluate the immunogenicity and safety of the CoronaVac inactivated COVID-19 vaccine in elderly patients with underlying medical conditions in China. Most patients show comparable neutralizing antibody and SARS-CoV-2-specific T cell responses to healthy controls, and no serious adverse effects are seen.
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- 2022
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17. Editorial: Deleterious and beneficial humoral immune response in viral diseases: Two sides of the same coin
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Feng-Liang Liu, Yuejin Liang, Pengfei Wang, and Yong-Tang Zheng
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antibodies ,viral diseases ,humoral immune response ,animal models ,vaccine ,adjuvants ,Immunologic diseases. Allergy ,RC581-607 - Published
- 2023
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18. Longitudinal analysis of immunocyte responses and inflammatory cytokine profiles in SFTSV-infected rhesus macaques
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Yi-Hui Li, Wen-Wu Huang, Wen-Qiang He, Xiao-Yan He, Xue-Hui Wang, Ya-Long Lin, Zu-Jiang Zhao, Yong-Tang Zheng, and Wei Pang
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SFTSV ,non-human primates ,rhesus macaques ,inflammatory cytokines ,immunocyte subsets ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Severe fever with thrombocytopenia syndrome virus (SFTSV), an emerging bunyavirus, causes severe fever with thrombocytopenia syndrome (SFTS), with a high fatality rate of 20%–30%. At present, however, the pathogenesis of SFTSV remains largely unclear and no specific therapeutics or vaccines against its infection are currently available. Therefore, animal models that can faithfully recapitulate human disease are important to help understand and treat SFTSV infection. Here, we infected seven Chinese rhesus macaques (Macaca mulatta) with SFTSV. Virological and immunological changes were monitored over 28 days post-infection. Results showed that mild symptoms appeared in the macaques, including slight fever, thrombocytopenia, leukocytopenia, increased aspartate aminotransferase (AST) and creatine kinase (CK) in the blood. Viral replication was persistently detectable in lymphoid tissues and bone marrow even after viremia disappeared. Immunocyte detection showed that the number of T cells (mainly CD8+ T cells), B cells, natural killer (NK) cells, and monocytes decreased during infection. In detail, effector memory CD8+ T cells declined but showed increased activation, while both the number and activation of effector memory CD4+ T cells increased significantly. Furthermore, activated memory B cells decreased, while CD80+/CD86+ B cells and resting memory B cells (CD27+CD21+) increased significantly. Intermediate monocytes (CD14+CD16+) increased, while myeloid dendritic cells (mDCs) rather than plasmacytoid dendritic cells (pDCs) markedly declined during early infection. Cytokines, including interleukin-6 (IL-6), interferon-inducible protein-10 (IP-10), and macrophage inflammatory protein 1 (MCP-1), were substantially elevated in blood and were correlated with activated CD4+ T cells, B cells, CD16+CD56+ NK cells, CD14+CD16+ monocytes during infection. Thus, this study demonstrates that Chinese rhesus macaques infected with SFTSV resemble mild clinical symptoms of human SFTS and provides detailed virological and immunological parameters in macaques for understanding the pathogenesis of SFTSV infection.
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- 2023
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19. CoVac501, a self-adjuvanting peptide vaccine conjugated with TLR7 agonists, against SARS-CoV-2 induces protective immunity
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Yiru Long, Jianhua Sun, Tian-Zhang Song, Tingting Liu, Feng Tang, Xinxin Zhang, Longfei Ding, Yunqiu Miao, Weiliang Zhu, Xiaoyan Pan, Qi An, Mian Qin, Xiankun Tong, Xionghua Peng, Pan Yu, Peng Zhu, Jianqing Xu, Xiaoyan Zhang, Yachun Zhang, Datao Liu, Ben Chen, Huilin Chen, Leike Zhang, Gengfu Xiao, Jianping Zuo, Wei Tang, Ji Zhou, Heng Li, Zhijian Xu, Hong-Yi Zheng, Xin-Yan Long, Qiuping Qin, Yong Gan, Jin Ren, Wei Huang, Yong-Tang Zheng, Guangyi Jin, and Likun Gong
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Cytology ,QH573-671 - Abstract
Abstract Safe, effective, and economical vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are needed to achieve adequate herd immunity and end the pandemic. We constructed a novel SARS-CoV-2 vaccine, CoVac501, which is a self-adjuvanting peptide vaccine conjugated with Toll-like receptor 7 (TLR7) agonists. The vaccine contains immunodominant peptides screened from the receptor-binding domain (RBD) and is fully chemically synthesized. It has been formulated in an optimized nanoemulsion formulation and is stable at 40 °C for 1 month. In non-human primates (NHPs), CoVac501 elicited high and persistent titers of protective neutralizing antibodies against multiple RBD mutations, SARS-CoV-2 original strain, and variants (B.1.1.7 and B.1.617.2). Specific peptides booster immunization against the B.1.351 variant has also been shown to be effective in improving protection against B.1.351. Meanwhile, CoVac501 elicited the increase of memory T cells, antigen-specific CD8+ T-cell responses, and Th1-biased CD4+ T-cell immune responses in NHPs. Notably, at an extremely high SARS-CoV-2 challenge dose of 1 × 107 TCID50, CoVac501 provided near-complete protection for the upper and lower respiratory tracts of cynomolgus macaques.
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- 2022
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20. SARS-CoV-2-triggered mast cell rapid degranulation induces alveolar epithelial inflammation and lung injury
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Meng-Li Wu, Feng-Liang Liu, Jing Sun, Xin Li, Xiao-Yan He, Hong-Yi Zheng, Yan-Heng Zhou, Qihong Yan, Ling Chen, Guo-Ying Yu, Junbiao Chang, Xia Jin, Jincun Zhao, Xin-Wen Chen, Yong-Tang Zheng, and Jian-Hua Wang
- Subjects
Medicine ,Biology (General) ,QH301-705.5 - Abstract
A schematic illustration of SARS-CoV-2 triggers MC rapid degranulation to induce alveolar epithelial inflammation and lung injury. SARS-CoV-2 triggers an immediate mast cell (MC) degranulation, which initiates the alveolar epithelial inflammation and disrupts the tight junction. MC stabilizers that block degranulation reduce virus-induced lung inflammation and injury.
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- 2021
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21. Identification of 6ω-cyclohexyl-2-(phenylamino carbonylmethylthio)pyrimidin-4(3H)-ones targeting the ZIKV NS5 RNA dependent RNA polymerase
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Guang-Feng Zhou, Cong-Qiang Xie, Jian-Xia Xue, Jing-Bo Wang, Yu-Zhuo Yang, Chang-Bo Zheng, Rong-Hua Luo, Ren-Hua Yang, Wen Chen, Liu-Meng Yang, Yue-Ping Wang, Hong-Bin Zhang, Yan-Ping He, and Yong-Tang Zheng
- Subjects
ZIKV ,RdRp ,acetylarylamine-S-DACOs ,anti-ZIKV agent ,NS5 ,Chemistry ,QD1-999 - Abstract
Zika virus (ZIKV), a mosquito-borne flavivirus, is a global health concern because of its association with severe neurological disorders such as neonatal microcephaly and adult Guillain-Barre syndrome. Although many efforts have been made to combat ZIKV infection, there is currently no approved vaccines or antiviral drugs available and there is an urgent need to develop effective anti-ZIKV agents. In this study, 26 acetylarylamine-S-DACOs derivatives were prepared, and eight of them were found to have inhibitory activity against Zika virus. Among these substances, 2-[(4-cyclohexyl-5-ethyl-6-oxo-1,6-dihydropyrimidin-2-yl)thio]-N-(3,5-difluorophenyl)acetamide (4w) with the best anti-ZIKV activity was selected for in-depth study of antiviral activity and mechanism of action. Here, we discovered 4w targeted on the ZIKV NS5 RNA -dependent RNA polymerase (RdRp), which exhibited good in vitro antiviral activity without cell species specificity, both at the protein level and at the RNA level can significantly inhibit ZIKV replication. Preliminary molecular docking studies showed that 4w preferentially binds to the palm region of NS5A RdRp through hydrogen bonding with residues such as LYS468, PHE466, GLU465, and GLY467. ZIKV NS5 RdRp enzyme activity experiment showed that 4w could directly inhibit ZIKV RdRp activity with EC50 = 11.38 ± 0.51 μM. In antiviral activity studies, 4w was found to inhibit ZIKV RNA replication with EC50 = 6.87 ± 1.21 μM. ZIKV-induced plaque formation was inhibited with EC50 = 7.65 ± 0.31 μM. In conclusion, our study disclosed that acetylarylamine-S-DACOs is a new active scaffolds against ZIKV, among which compound 4w was proved to be a potent novel anti-ZIKV compound target ZIKV RdRp protein. These promising results provide a future prospective for the development of ZIKV RdRp inhibitors.
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- 2022
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22. Pro-inflammatory microenvironment and systemic accumulation of CXCR3+ cell exacerbate lung pathology of old rhesus macaques infected with SARS-CoV-2
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Hong-Yi Zheng, Xiao-Yan He, Wei Li, Tian-Zhang Song, Jian-Bao Han, Xiang Yang, Feng-Liang Liu, Rong-Hua Luo, Ren-Rong Tian, Xiao-Li Feng, Yu-Hua Ma, Chao Liu, Ming-Hua Li, and Yong-Tang Zheng
- Subjects
Medicine ,Biology (General) ,QH301-705.5 - Abstract
Abstract Understanding the pathological features of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in an animal model is crucial for the treatment of coronavirus disease 2019 (COVID-19). Here, we compared immunopathological changes in young and old rhesus macaques (RMs) before and after SARS-CoV-2 infection at the tissue level. Quantitative analysis of multiplex immunofluorescence staining images of formalin-fixed paraffin-embedded (FFPE) sections showed that SARS-CoV-2 infection specifically induced elevated levels of apoptosis, autophagy, and nuclear factor kappa-B (NF-κB) activation of angiotensin-converting enzyme 2 (ACE2)+ cells, and increased interferon α (IFN-α)- and interleukin 6 (IL-6)-secreting cells and C-X-C motif chemokine receptor 3 (CXCR3)+ cells in lung tissue of old RMs. This pathological pattern, which may be related to the age-related pro-inflammatory microenvironment in both lungs and spleens, was significantly correlated with the systemic accumulation of CXCR3+ cells in lungs, spleens, and peripheral blood. Furthermore, the ratio of CXCR3+ to T-box protein expression in T cell (T-bet)+ (CXCR3+/T-bet+ ratio) in CD8+ cells may be used as a predictor of severe COVID-19. These findings uncovered the impact of aging on the immunopathology of early SARS-CoV-2 infection and demonstrated the potential application of CXCR3+ cells in predicting severe COVID-19.
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- 2021
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23. Consistency of spatial dynamics of HIV-1 and HCV among HIV-1/HCV coinfected drug users in China
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Yu Wang, Xin Chen, Mei Ye, Wei Pang, Chiyu Zhang, Si-Dong Xiong, and Yong-Tang Zheng
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HIV-1 ,HCV ,Spatial dynamic ,Coinfection ,Drug users ,Yunnan ,Infectious and parasitic diseases ,RC109-216 - Abstract
Abstract Background As the transmission routes of human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV) are similar, previous studies based on separate research on HIV-1 and HCV assumed a similar transmission pattern. However, few studies have focused on the possible correlation of the spatial dynamics of HIV-1 and HCV among HIV-1/HCV coinfected patients. Methods A total of 310 HIV-1/HCV coinfected drug users were recruited in Yingjiang and Kaiyuan prefectures, Yunnan Province, China. HIV-1 env, p17, pol and HCV C/E2, NS5B fragments were amplified and sequenced from serum samples. The genetic characteristics and spatial dynamics of HIV-1 and HCV were explored by phylogenetic, bootscanning, and phylogeographic analyses. Results Among HIV-1/HCV coinfected drug users, eight HCV subtypes (1a, 1b, 3a, 3b, 6a, 6n, 6v, and 6u) and two HIV-1 subtypes (subtype B and subtype C), three HIV-1 circulating recombinant forms (CRF01_AE, CRF07_BC and CRF08_BC), and four unique recombinant forms (URF_BC, URF_01B, URF_01C and URF_01BC) were identified. HCV subtype 3b was the most predominant subtype in both Yingjiang and Kaiyuan prefectures. The dominant circulating HIV-1 subtypes for drug users among the two areas were CRF08_BC and URF_BC. Maximum clade credibility trees revealed that both HIV-1 and HCV were transmitted from Yingjiang to Kaiyuan. Conclusions The spatial dynamics of HIV-1 and HCV among HIV-1/HCV coinfected drug users seem to have high consistency, providing theoretical evidence for the prevention of HIV-1 and HCV simultaneously.
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- 2021
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24. Modification of N-terminal α-amine of proteins via biomimetic ortho-quinone-mediated oxidation
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Siyao Wang, Qingqing Zhou, Xiaoping Chen, Rong-Hua Luo, Yunxue Li, Xinliang Liu, Liu-Meng Yang, Yong-Tang Zheng, and Ping Wang
- Subjects
Science - Abstract
Methods for selective modification of the N-terminus of proteins are of high interest, but mostly require specific amino acid residues. Here, the authors report a selective and fast method for N-terminal modification of proteins based on quinone-mediated oxidation of the alpha-amine to aldehyde or ketone, and apply it to diverse proteins.
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- 2021
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25. S-Trimer, a COVID-19 subunit vaccine candidate, induces protective immunity in nonhuman primates
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Joshua G. Liang, Danmei Su, Tian-Zhang Song, Yilan Zeng, Weijin Huang, Jinhua Wu, Rong Xu, Peiwen Luo, Xiaofang Yang, Xiaodong Zhang, Shuangru Luo, Ying Liang, Xinglin Li, Jiaju Huang, Qiang Wang, Xueqin Huang, Qingsong Xu, Mei Luo, Anliang Huang, Dongxia Luo, Chenyan Zhao, Fan Yang, Jian-Bao Han, Yong-Tang Zheng, and Peng Liang
- Subjects
Science - Abstract
Vaccines for SARS-CoV-2 are needed to fight the pandemic. Here the authors show immunogenicity of an adjuvanted subunit vaccine, SARS-CoV-2 spike protein trimerized with trimer-tag technology, in small animal models and protection from SARS-CoV-2 challenge in non-human primates.
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- 2021
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26. Longitudinal transcriptome analyses show robust T cell immunity during recovery from COVID-19
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Hong-Yi Zheng, Min Xu, Cui-Xian Yang, Ren-Rong Tian, Mi Zhang, Jian-Jian Li, Xi-Cheng Wang, Zhao-Li Ding, Gui-Mei Li, Xiao-Lu Li, Yu-Qi He, Xing-Qi Dong, Yong-Gang Yao, and Yong-Tang Zheng
- Subjects
Medicine ,Biology (General) ,QH301-705.5 - Abstract
Abstract Understanding the processes of immune regulation in patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is crucial for improving treatment. Here, we performed longitudinal whole-transcriptome RNA sequencing on peripheral blood mononuclear cell (PBMC) samples from 18 patients with coronavirus disease 2019 (COVID-19) during their treatment, convalescence, and rehabilitation. After analyzing the regulatory networks of differentially expressed messenger RNAs (mRNAs), microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) between the different clinical stages, we found that humoral immunity and type I interferon response were significantly downregulated, while robust T-cell activation and differentiation at the whole transcriptome level constituted the main events that occurred during recovery from COVID-19. The formation of this T cell immune response might be driven by the activation of activating protein-1 (AP-1) related signaling pathway and was weakly affected by other clinical features. These findings uncovered the dynamic pattern of immune responses and indicated the key role of T cell immunity in the creation of immune protection against this disease.
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- 2020
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27. CircGRIA1 shows an age-related increase in male macaque brain and regulates synaptic plasticity and synaptogenesis
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Kaiyu Xu, Ying Zhang, Wandi Xiong, Zhongyu Zhang, Zhengbo Wang, Longbao Lv, Chao Liu, Zhengfei Hu, Yong-Tang Zheng, Lin Lu, Xin-Tian Hu, and Jiali Li
- Subjects
Science - Abstract
Circular RNAs are expressed in the brain and show age-dependent expression patterns. Here the authors show the circGRIA1 is expressed in an age-dependent manner in the male macaque brain and serves a functional role in synaptic plasticity.
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- 2020
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28. Daphnane Diterpenoids from Trigonostemon lii and Inhibition Activities Against HIV-1
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Cheng-Jian Tan, Shi-Fei Li, Ning Huang, Yu Zhang, Ying-Tong Di, Yong-Tang Zheng, and Xiao-Jiang Hao
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Trigonostemon lii ,Daphnane diterpenoid ,Trigonolactone ,Anti-HIV ,Botany ,QK1-989 - Abstract
Abstract Natural products are the important source for the discovery of more potent anti-HIV agents. In this study, six daphnane diterpenoids including three unreported structures were isolated from Trigonostemon lii, which showed significant activities against HIV-1 strains replication in the nanomolar/picomolar range. Meanwhile, these diterpenoids significantly inhibited the fusion of H9/HIV-1 IIIB cells with uninfected C8166 cells, with the EC50s from 1.06 to 8.73 ng/mL, and did not show any inhibition activities against HIV-1 reverse transcriptase. Moreover, all of the diterpenoids shows significant inhibitions against T20-resistan HIV-1 strains, PNL4-3gp41(36G)V38E, N42S and pNL4-3gp41(36G)V38A, N42T. The results revealed that the six diterpenoids could be a new type of potential lead candidate as an HIV entry inhibitor, particularly for those infected by T20-resistant variants. Graphic Abstract
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- 2020
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29. Glucose Metabolism Disorder Induces Spermatogenic Dysfunction in Northern Pig-Tailed Macaques (Macaca leonina) With Long-Term SIVmac239 Infection
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Tian-Zhang Song, Ming-Xu Zhang, Han-Dan Zhang, Xue-Hui Wang, Wei Pang, Ren-Rong Tian, and Yong-Tang Zheng
- Subjects
spermatogenic dysfunction ,glucose metabolism ,Macaca leonina ,northern pig-tailed macaques ,SIVmac239 ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
Although spermatogenic dysfunction is widely found in patients with human immunodeficiency virus (HIV), the underlying reasons remain unclear. Thus far, potential hypotheses involving viral reservoirs, testicular inflammation, hormone imbalance, and cachexia show inconsistent correlation with spermatogenic dysfunction. Here, northern pig-tailed macaques (NPMs) exhibited marked spermatogenic dysfunction after long-term infection with simian immunodeficiency virus (SIVmac239), with significant decreases in Johnsen scores, differentiated spermatogonial stem cells, and testicular proliferating cells. The above hypotheses were also evaluated. Results showed no differences between SIV− and SIV+ NPMs, except for an increase in follicle stimulating hormone (FSH) during SIV infection, which had no direct effect on the testes. However, long-term SIVmac239 infection undermined pancreatic islet β cell function, partly represented by significant reductions in cellular counts and autophagy levels. Pancreatic islet β cell dysfunction led to glucose metabolism disorder at the whole-body level, which inhibited lactate production by Sertoli cells in testicular tissue. As lactate is the main energy substrate for developing germ cells, its decrease was strongly correlated with spermatogenic dysfunction. Therefore, glucose metabolism disorder appears to be a primary cause of spermatogenic dysfunction in NPMs with long-term SIVmac239 infection.
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- 2021
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30. A recombinant receptor-binding domain in trimeric form generates protective immunity against SARS-CoV-2 infection in nonhuman primates
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Limin Yang, Deyu Tian, Jian-bao Han, Wenhui Fan, Yuan Zhang, Yunlong Li, Wenqiang Sun, Yanqiu Wei, Xiaodong Tian, Dan-dan Yu, Xiao-li Feng, Gong Cheng, Yuhai Bi, Yong-tang Zheng, and Wenjun Liu
- Subjects
COVID-19 ,SARS-CoV-2 ,RBD ,subunit vaccine ,NHPs ,variants ,Science (General) ,Q1-390 - Abstract
Summary: A safe and effective vaccine is critical to combat the COVID-19 pandemic. Here, we developed a trimeric SARS-CoV-2 receptor-binding domain (RBD) subunit vaccine candidate that simulates the natural structure of the spike (S) trimer glycoprotein. Immunization with the RBD trimer-induced robust humoral and cellular immune responses, and a high level of neutralizing antibodies was maintained for at least 4.5 months. Moreover, the antibodies that were produced in response to the vaccine effectively cross-neutralized the SARS-CoV-2 501Y.V2 variant (B.1.351). Of note, when the vaccine-induced antibodies dropped to a sufficiently low level, only one boost quickly activated the anamnestic immune response, conferring full protection against a SARS-CoV-2 challenge in rhesus macaques without typical histopathological changes in the lung tissues. These results demonstrated that the SARS-CoV-2 RBD trimer vaccine candidate is highly immunogenic and safe, providing long-lasting, broad, and significant immunity protection in nonhuman primates, thereby offering an optimal vaccination strategy against COVID-19. Public summary: • A SARS-CoV-2 trimeric vaccine candidate demonstrates safe, long-lasting, broad, and significant immunity protection in nonhuman primates • The vaccine-induced antibodies can effectively neutralize the SARS-CoV-2 501Y.V2 variant • A booster vaccination can quickly activate the memory immune response to avoid re-infection
- Published
- 2021
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31. Burmese injecting drug users in Yunnan play a pivotal role in the cross-border transmission of HIV-1 in the China-Myanmar border region
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Xin Chen, Yan-Heng Zhou, Mei Ye, Yu Wang, Lin Duo, Wei Pang, Chiyu Zhang, and Yong-Tang Zheng
- Subjects
HIV-1 ,IDUs ,cross-border ,transmission ,epidemiology ,China ,Myanmar ,Infectious and parasitic diseases ,RC109-216 - Abstract
Injecting drug users (IDUs) are the major risk group for HIV-1 infection in the China-Myanmar border area. There are a large number of Burmese IDUs living in Yunnan (Yunnan-mIDUs) who might be associated with the cross-border transmission of HIV-1. From 2010 to 2013, 617 Yunnan-mIDUs were recruited from three counties of Yunnan, 19.0% of whom were detected to be HIV-1 positive by serological testing. Partial HIV-1 p17, pol, vif-env, and env genes were amplified from the positive samples and were sequenced. Phylogenetic and HIV-1 subtyping analyses revealed that HIV-1 recombinant forms (RFs), including RF_BC (36.4%), RF_01BC (26.1%), RF_01C (9.1%) and RF_01B (1.1%), were predominant among this cohort. Of the identified HIV-1 strains, 14.8%, 9.1% and 3.4% belonged to subtype C, CRF01_AE and subtype B, respectively. Transmission cluster analysis showed that sequences from the Yunnan-mIDUs formed transmission clusters not only with those from Burmese IDUs but also with those from Chinese IDUs, indicating that Yunnan-mIDUs might acquire HIV-1 infection from or spread HIV-1 to both Burmese and Chinese IDUs. Phylogeographic analyses revealed three cross-border transmission patterns associated with Yunnan-mIDUs, in which Yunnan-mIDUs served as the crucial nodes linking the Burmese and Chinese IDUs. These results suggest that Yunnan-mIDUs are a potential viral reservoir for the diffusion of HIV-1 in Yunnan and play a pivotal role in the bidirectional cross-border transmission of HIV-1 in the China-Myanmar border region. More intervention efforts that focus on Yunnan-mIDUs are recommended in Yunnan’s campaign against HIV/AIDS.
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- 2018
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32. Transcription Factor ZNF683 Inhibits SIV/HIV Replication through Regulating IFNγ Secretion of CD8+ T Cells
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Ying Lu, Ming-Xu Zhang, Wei Pang, Tian-Zhang Song, Hong-Yi Zheng, Ren-Rong Tian, and Yong-Tang Zheng
- Subjects
lung ,SIVmac239 ,slow progressors ,rapid progressors ,northern pig-tailed macaques ,ZNF683 ,Microbiology ,QR1-502 - Abstract
Pulmonary microbial invasion frequently occurs during AIDS progression in HIV patients. Inflammatory cytokines and other immunoregulatory factors play important roles in this process. We previously established an AIDS model of SIVmac239 infection in northern pig-tailed macaques (NPMs), which were divided into rapid progressor (RP) and slow progressor (SP) groups according to their AIDS progression rates. In this study, we performed 16S rDNA and transcriptome sequencing of the lungs to reveal the molecular mechanism underlying the difference in progression rate between the RPs and SPs. We found that microbial invasion in the RP group was distinct from that in the SP group, showing marker flora of the Family XI, Enterococcus and Ezakiella, and more Lactobacilli. Through pulmonary transcriptome analysis, we found that the transcription factor ZNF683 had higher expression in the SP group than in the RP group. In subsequent functional experiments, we found that ZNF683 increased the proliferation and IFNγ secretion ability of CD8+ T cells, thus decreasing SIV or HIV replication, which may be related to AIDS progression in SIVmac239-infected NPMs. This study helps elucidate the various complexities of disease progression in HIV-1-infected individuals.
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- 2022
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33. Bromodomain and Extra-Terminal Inhibitor BMS-986158 Reverses Latent HIV-1 Infection In Vitro and Ex Vivo by Increasing CDK9 Phosphorylation and Recruitment
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Xu-Sheng Huang, Ren-Rong Tian, Meng-Di Ma, Rong-Hua Luo, Liu-Meng Yang, Guang-Hui Peng, Mi Zhang, Xing-Qi Dong, and Yong-Tang Zheng
- Subjects
HIV-1 ,BET ,BMS-986158 ,latency reversing agent ,latent reservoir ,Medicine ,Pharmacy and materia medica ,RS1-441 - Abstract
Latent reservoir persistence remains a major obstacle for curing human immunodeficiency virus type 1 (HIV-1) infection. Thus, strategies for the elimination of latent HIV-1 are urgently needed. As a bromodomain and extra-terminal (BET) inhibitor, BMS-986158 has been used in clinical trials for advanced solid tumors and hematological malignancies. Here, we found that BMS-986158 reactivated latent HIV-1 in three types of HIV-1 latency cells in vitro, and in combination antiretroviral therapy (cART)-treated patient-derived peripheral blood mononuclear cells ex vivo, without influencing global immune cell activation. BMS-986158 reactivated latent HIV-1 by increasing phosphorylation of CDK9 at Thr186 and promoting recruitment of CDK9 and RNA polymerase II to the HIV-1 long terminal repeat in J-Lat cells. Furthermore, BMS-986158 exerted strong synergism in reactivating latent HIV-1 when combined with prostratin and vorinostat and enhanced the antiviral activity of anti-HIV-1 drugs. Finally, BMS-986158 showed antiviral activity in an HIV-1 acute infection model, possibly by arresting the cell cycle in infected cells. Thus, these results suggest that BMS-986158 is a potential candidate for AIDS/HIV-1 therapy.
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- 2022
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34. Lyophyllin, a Mushroom Protein from the Peptidase M35 Superfamily Is an RNA N-Glycosidase
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Jia-Qi Lu, Wei-Wei Shi, Meng-Jie Xiao, Yun-Sang Tang, Yong-Tang Zheng, and Pang-Chui Shaw
- Subjects
ribosome-inactivating proteins ,lyophyllin ,peptidase M35 superfamily ,N-glycosidase ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Ribosome-inactivating proteins (RIPs) hydrolyze the N-glycosidic bond and depurinate a specific adenine residue (A-4324 in rat 28S ribosomal RNA, rRNA) in the conserved α-sarcin/ricin loop (α-SRL) of rRNA. In this study, we have purified and characterized lyophyllin, an unconventional RIP from Lyophyllum shimeji, an edible mushroom. The protein resembles peptidase M35 domain of peptidyl-Lys metalloendopeptidases. Nevertheless, protein either from the mushroom or in recombinant form possessed N-glycosidase and protein synthesis inhibitory activities. A homology model of lyophyllin was constructed. It was found that the zinc binding pocket of this protein resembles the catalytic cleft of a classical RIP, with key amino acids that interact with the adenine substrate in the appropriate positions. Mutational studies showed that E122 may play a role in stabilizing the positively charged oxocarbenium ion and H121 for protonating N-3 of adenine. The tyrosine residues Y137 and Y104 may be used for stacking the target adenine ring. This work first shows a protein in the peptidase M35 superfamily based on conserved domain search possessing N-glycosidase activity.
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- 2021
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35. Accelerated disease progression and robust innate host response in aged SIVmac239-infected Chinese rhesus macaques is associated with enhanced immunosenescence
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Hong-Yi Zheng, Ming-Xu Zhang, Min Chen, Jin Jiang, Jia-Hao Song, Xiao-Dong Lian, Ren-Rong Tian, Xiao-Liang Zhang, Lin-Tao Zhang, Wei Pang, Gao-Hong Zhang, and Yong-Tang Zheng
- Subjects
Medicine ,Science - Abstract
Abstract The elderly population infected with HIV-1 is often characterized by the rapid AIDS progression and poor treatment outcome, possibly because of immunosenescence resulting from both HIV infection and aging. However, this hypothesis remains to be fully tested. Here, we studied 6 young and 12 old Chinese rhesus macaques (ChRM) over the course of three months after simian immunodeficiency virus (SIV) SIVmac239 infection. Old ChRM showed a higher risk of accelerated AIDS development than did young macaques, owing to rapidly elevated plasma viral loads and decreased levels of CD4+ T cells. The low frequency of naïve CD4+ T cells before infection was strongly predictive of an increased disease progression, whereas the severe depletion of CD4+ T cells and the rapid proliferation of naïve lymphocytes accelerated the exhaustion of naïve lymphocytes in old ChRM. Moreover, in old ChRM, a robust innate host response with defective regulation was associated with a compensation for naïve T cell depletion and a high level of immune activation. Therefore, we suggest that immunosenescence plays an important role in the accelerated AIDS progression in elderly individuals and that SIV-infected old ChRM may be a favorable model for studying AIDS pathogenesis and researching therapies for elderly AIDS patients.
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- 2017
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36. Identification of a New HCV Subtype 6xg Among Injection Drug Users in Kachin, Myanmar
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Mei Ye, Xin Chen, Yu Wang, Lin Duo, Chiyu Zhang, and Yong-Tang Zheng
- Subjects
hepatitis C virus ,injection drug users ,subtype ,HCV 6xg ,Myanmar ,Yunnan ,Microbiology ,QR1-502 - Abstract
Characterizing hepatitis C virus (HCV) genetic diversity not only allows us to trace its origin and evolutionary history, but also provides valuable insights into diagnosis, prevention and therapy of HCV infection. Although eight HCV genotypes and 86 subtypes have been classified, there are still some HCV variants that need to be assigned. The genotype 6 is the most diverse HCV genotype and mainly prevalent in Southeast Asia. In this study, we identified a new HCV subtype 6xg from injection drug users (IDUs) in Kachin, Myanmar. A distinctive feature of 6xg from other subtypes of the genotype 6 was a Lys insertion in NS5A gene, which changes the RRKR/K motif into RRKKR/K. Bayesian analyses showed that HCV 6xg originated during 1984–1988, and experienced a rapid population expansion during 2005–2009. We characterized HCV subtype profile among IDUs in this region, and detected six HCV subtypes, including 1a (12.0%), 3a (12.0%), 3b (24.0%), 6n (16.0%), 6xa (20.0%), and 6xg (12.0%). Importantly, we found that HCV subtype distribution in Kachin was very similar to that in Dehong prefecture of Yunnan, but very distinct from those in other regions of Myanmar and Yunnan, indicating that the China–Myanmar border region shared a unique HCV subtype pattern. The appearance of 6xg and the unique HCV subtype profile among IDUs in the China–Myanmar border region have significant epidemiological and public health implications.
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- 2019
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37. Engineering of Ribosome-inactivating Proteins for Improving Pharmacological Properties
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Jia-Qi Lu, Zhen-Ning Zhu, Yong-Tang Zheng, and Pang-Chui Shaw
- Subjects
ribosome inactivating protein ,therapeutic applications ,immunotoxin ,anti-hiv ,anti-cancer ,Medicine - Abstract
Ribosome-inactivating proteins (RIPs) are N-glycosidases, which depurinate a specific adenine residue in the conserved α-sarcin/ricin loop (α-SRL) of rRNA. This loop is important for anchoring elongation factor (EF-G for prokaryote or eEF2 for eukaryote) in mRNA translocation. Translation is inhibited after the attack. RIPs therefore may have been applied for anti-cancer, and anti-virus and other therapeutic applications. The main obstacles of treatment with RIPs include short plasma half-life, non-selective cytotoxicity and antigenicity. This review focuses on the strategies used to improve the pharmacological properties of RIPs on human immunodeficiency virus (HIV) and cancers. Coupling with polyethylene glycol (PEG) increases plasma time and reduces antigenicity. RIPs conjugated with antibodies to form immunotoxins increase the selective toxicity to target cells. The prospects for future development on the engineering of RIPs for improving their pharmacological properties are also discussed.
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- 2020
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38. Host Restriction Factors APOBEC3G/3F and Other Interferon-Related Gene Expressions Affect Early HIV-1 Infection in Northern Pig-Tailed Macaque (Macaca leonina)
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Wei Pang, Jia-Hao Song, Ying Lu, Xiao-Liang Zhang, Hong-Yi Zheng, Jin Jiang, and Yong-Tang Zheng
- Subjects
northern pig-tailed macaques ,HIV-1NL4-R3A ,stHIV-1sv ,neutralizing antibodies ,IFN-I signaling ,APOBEC3 ,Immunologic diseases. Allergy ,RC581-607 - Abstract
The northern pig-tailed macaques (NPMs) lack TRIM5α, an antiviral restriction factor, and instead have TRIM5-CypA. In our previous study, we demonstrated that HIV-1NL4−3 successfully infected NPMs and formed a long-term viral reservoir in vivo. However, the HIV-1-infected NPMs showed relatively high viremia in the first 6 weeks of infection, which declined thereafter suggesting that HIV-1 NL4−3 infection in these animals was only partly permissive. To optimize HIV-1 infection in NPMs therefore, we generated HIV-1NL4−R3A and stHIV-1sv, and infected NPMs with these viruses. HIV-1NL4−R3A and stHIV-1sv can replicate persistently in NPMs during 41 weeks of acute infection stage. Compared to the HIV-1NL4−R3A, stHIV-1sv showed a notably higher level of replication, and the NPMs infected with the latter induced a more robust neutralizing antibody but a weaker cellular immune response. In addition, IFN-I signaling was significantly up-regulated with the viral replication, and was higher in the stHIV-1sv infected macaques. Consequently, the sequences of pro-viral env showed fewer G-A hyper-mutations in stHIV-1sv, suggesting that vif gene of SIV could antagonize the antiviral effects of APOBEC3 proteins in NPMs. Taken together, NPMs infected with HIV-1NL4−R3A and stHIV-1sv show distinct virological and immunological features. Furthermore, interferon-related gene expression might play a role in controlling primary HIV-1NL4−R3A and stHIV-1sv replication in NPMs. This result suggests NPM is a potential HIV/AIDS animal model.
- Published
- 2018
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39. The Recombinant Maize Ribosome-Inactivating Protein Transiently Reduces Viral Load in SHIV89.6 Infected Chinese Rhesus Macaques
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Rui-Rui Wang, Ka-Yee Au, Hong-Yi Zheng, Liang-Min Gao, Xuan Zhang, Rong-Hua Luo, Sue Ka-Yee Law, Amanda Nga-Sze Mak, Kam-Bo Wong, Ming-Xu Zhang, Wei Pang, Gao-Hong Zhang, Pang-Chui Shaw, and Yong-Tang Zheng
- Subjects
maize RIP ,anti-HIV ,animal model ,viral load ,Medicine - Abstract
Ribosome inactivating proteins (RIPs) inhibit protein synthesis by depurinating the large ribosomal RNA and some are found to possess anti-human immunodeficiency virus (HIV) activity. Maize ribosome inactivating protein (RIP) has an internal inactivation loop which is proteolytically removed for full catalytic activity. Here, we showed that the recombinant active maize RIP protected chimeric simian-human immunodeficiency virus (SHIV) 89.6-infected macaque peripheral blood mononuclear cells from lysis ex vivo and transiently reduced plasma viral load in SHIV89.6-infected rhesus macaque model. No evidence of immune dysregulation and other obvious side-effects was found in the treated macaques. Our work demonstrates the potential development of maize RIP as an anti-HIV agent without impeding systemic immune functions.
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- 2015
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40. HCV Diversity among Chinese and Burmese IDUs in Dehong, Yunnan, China.
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Zhenzhou Wan, Qianqian Chen, Xin Chen, Lin Duo, Peilu Li, Yong-Tang Zheng, and Chiyu Zhang
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Medicine ,Science - Abstract
HCV transmission is closely associated with drug-trafficking routes in China. Dehong, a prefecture of Yunnan, is the important trade transfer station linking Southeast Asia and China, as well as the drug-trafficking channel linking "Golden triangle" and other regions of China and surrounding countries. In this study, we investigated the HCV genotype diversity among IDUs in Dehong based on 259 HCV positive samples from 118 Chinese and 141 Burmese IDUs. HCV genotypes were determined based on the phylogenies of C/E2 and NS5B genomic sequences. Six HCV subtypes, including 1a, 1b, 3a, 3b, 6n and 6u, were detected. Interestingly, 4 HCV sequences from Burmese IDUs did not cluster with any known HCV subtypes, but formed a well-supported independent clade in the phylogenetic trees of both C/E2 and NS5B, suggesting a potential new HCV subtype circulating in Dehong. Subtype 3b was the predominant subtype, followed by subtypes 6n and 6u. Comparison showed that Dehong had a unique pattern of HCV subtype distribution, obviously different from other regions of China. In particular, HCV subtypes 6u and the potential new HCV subtype had a relatively high prevalence in Dehong, but were rarely detected in other regions of China. There was no significant difference in HCV subtype distribution between Burmese and Chinese IDUs. Few HCV sequences from Burmese and Chinese IDUs clustered together to form transmission clusters. Furthermore, about half of HCV sequences from Burmese IDUs formed small transmission clusters, significantly higher than that from Chinese IDUs (p
- Published
- 2016
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41. Potent Anti-HIV Activities and Mechanisms of Action of a Pine Cone Extract from Pinus yunnanensis
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Yong-Tang Zheng, Hao-Zhi Li, Ya-Juan Liu, Guang-Ming Liu, Xuan Zhang, Liu-Meng Yang, Chang-Bo Zheng, and Yong-Jun Lv
- Subjects
Pinus yunnanensis ,pine cone ,anti-HIV activity ,reverse transcriptase ,fusion ,Organic chemistry ,QD241-441 - Abstract
The anti-HIV activities of a pine cone extract (YNS-PY-F) from Pinus yunnanensis have been evaluated, and its mechanisms of action were also explored. The pine cone extract, YNS-PY-F, potently inhibited HIV-1IIIB, HIV-1RF, HIV-1A17, HIV-1AO18 and HIV-2ROD and induced cytopathic effect in C8166 cells with EC50 values of 0.96 μg/mL, 1.53 μg/mL, 0.88 μg/mL, 7.20 μg/mL and 6.17 μg/mL, respectively. The quantification of a p24 production assay showed that YNS-PY-F significantly inhibited the acute replication of HIV-1IIIB, HIV-1RF, HIV-1A17 and HIV-1AO18 in C8166 cells. An MTT assay showed that YNS-PY-F also significantly inhibited the HIV-1IIIB induced cytolysis in MT-4 cells with an EC50 value of 2.22 μg/mL. The mechanism assays showed that YNS-PY-F had potent inhibitory effects on the fusion between infected cells and uninfected cells, and the activity of HIV-1 reverse transcriptase, with EC50 values of 7.60 μg/mL and 4.60 μg/mL, respectively. Overall, these data suggest that the pine cone extract from Pinus yunnanensis has potent inhibitory activities against HIV-1IIIB, HIV-1RF, RT inhibitor-resistant strains HIV-1A17 and HIV-1AO18, and HIV-2ROD, and its anti-HIV mechanisms include inhibition of HIV entry and inhibition of reverse transcriptase activity.
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- 2012
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42. Mangiferin, an Anti-HIV-1 Agent Targeting Protease and Effective against Resistant Strains
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Rui-Rui Wang, Yue-Dong Gao, Chun-Hui Ma, Xing-Jie Zhang, Cheng-Gang Huang, Jing-Fei Huang, and Yong-Tang Zheng
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mangiferin ,HIV-1 ,protease ,anti-HIV agents ,drug resistance ,Organic chemistry ,QD241-441 - Abstract
The anti-HIV-1 activity of mangiferin was evaluated. Mangiferin can inhibit HIV-1ⅢB induced syncytium formation at non-cytotoxic concentrations, with a 50% effective concentration (EC50) at 16.90 μM and a therapeutic index (TI) above 140. Mangiferin also showed good activities in other laboratory-derived strains, clinically isolated strains and resistant HIV-1 strains. Mechanism studies revealed that mangiferin might inhibit the HIV-1 protease, but is still effective against HIV peptidic protease inhibitor resistant strains. A combination of docking and pharmacophore methods clarified possible binding modes of mangiferin in the HIV-1 protease. The pharmacophore model of mangiferin consists of two hydrogen bond donors and two hydrogen bond acceptors. Compared to pharmacophore features found in commercially available drugs, three pharmacophoric elements matched well and one novel pharmacophore element was observed. Moreover, molecular docking analysis demonstrated that the pharmacophoric elements play important roles in binding HIV-1 protease. Mangiferin is a novel nonpeptidic protease inhibitor with an original structure that represents an effective drug development strategy for combating drug resistance.
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- 2011
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43. The Anti-HIV Actions of 7- and 10-Substituted Camptothecins
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Yu-Ye Li, Shi-Wu Chen, Liu-Meng Yang, Rui-Rui Wang, Wei Pang, and Yong-Tang Zheng
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camptothecin ,anti-HIV agents ,HIV ,Organic chemistry ,QD241-441 - Abstract
Camptothecin (CPT), a traditional anti-tumor drug, has been shown to possess anti-HIV-1 activity. To increase the antiviral potency, the anti-HIV activities of two CPT derivatives, 10-hydroxy-CPT and 7-hydroxymethyl-CPT, were evaluated in vitro. The therapy index (TI) of CPT, 10-hydroxy-CPT and 7-hydroxymethyl-CPT against HIV-1IIIB in C8166 were 24.2, 4.2 and 198.1, and against clinical isolated strain HIV-1KM018 in PBMC were 10.3, 3.5 and 66.0, respectively. While the TI of CPT, 10-hydroxy-CPT and 7-hydroxymethyl-CPT against HIV-2CBL-20 were 34.5, 10.7 and 317.0, respectively, and the TI of the three compounds against HIV-2ROD showed the similar values. However, when the antiviral mechanisms were considered, we found there was no inhibition of 7-hydroxymethyl-CPT on viral cell-to-cell transmission, and was no inhibition on reverse transcriptase, protease or integrase in cell-free systems. 7-Hydroxymethyl-CPT showed no selective killing of chronically infected cells after 3 days of incubation. In conclusion, 7-hydroxymethyl-CPT showed more potent anti-HIV activity, while 10-hydroxy-CPT had less efficient activity, compared with the parent CPT. Though the antiviral mechanisms remain to be further elucidated; the modification of -OH residues at C-7 of CPT could enhance the antiviral activity, while of -OH residues at C-10 of CPT had decreased the antiviral activity, which provides the preliminary modification strategy for anti-viral activities enhancement of this compound.
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- 2009
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44. Synthesis and Anti-Human Immunodeficiency Virus Type 1 Activity of (E)-N-Phenylstyryl-N-alkylacetamide Derivatives
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Pi Cheng, Ji-Jun Chen, Ning Huang, Rui-Rui Wang, Yong-Tang Zheng, and Yi-Zeng Liang
- Subjects
(E)-N-phenylstyryl-N-alkylacetamides ,synthesis ,reverse transcriptase ,anti-HIV-1 activity ,Organic chemistry ,QD241-441 - Abstract
A series of (E)-N-phenylstyryl-N-alkylacetamides, 5, were synthesized by direct reduction-acetylation of β-arylnitroolefins, followed by N-alkylation. The title compounds were characterized by 1H-NMR, EIMS and IR analysis. All the synthesized compounds were assayed as HIV-1 non-nucleoside reverse transcriptase inhibitors. A SAR study revealed that when group R1 in 5 was ortho-substituted, the resulting compounds showed better inhibitory activities against HIV-1 RT. Among the tested compounds, 5i (R1 = 2-Br, R2 = 3,5-difluorobenzyl) exhibited the highest enzyme activity, with a 88.89% inhibitory ratio against HIV-1 reverse transcriptase at the tested concentration. Further cell-based anti-HIV-1 assays showed that compound 5i exhibited a SI value of 29 with an EC50 value of 4 μM in C8166 cells.
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- 2009
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45. Two New Phenolic Glycosides from Viscum articulatum
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Xiao-Li Li, Yong-Ping Yang, Yong-Tang Zheng, Ning Huang, Yan-Li Zhao, and Yang Li
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Viscum articulatum ,Phenolic glycoside ,Flavanone ,Organic chemistry ,QD241-441 - Abstract
Two new phenolic glycosides, 1-O-benzyl-[5-O-benzoyl-β-D-apiofuranosyl (1→2)]-β-D-glucopyranoside (1), and 4`-hydroxy-7,3`-dimethoxyflavan-5-O- β-D-gluco-pyranoside (2), together with nine known flavanones 3 - 11, have been isolated from the dried whole plants of Viscum articulatum.Their structures were identified by extensive spectral analysis, especially 2D NMR techniques. Compound 9 showed weak anti-HIV-1 activity.
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- 2008
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46. Lipopolysaccharide Increases Immune Activation and Alters T Cell Homeostasis in SHIVB’WHU Chronically Infected Chinese Rhesus Macaque
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Gao-Hong Zhang, Run-Dong Wu, Hong-Yi Zheng, Xiao-Liang Zhang, Ming-Xu Zhang, Ren-Rong Tian, Guang-Ming Liu, Wei Pang, and Yong-Tang Zheng
- Subjects
Immunologic diseases. Allergy ,RC581-607 - Abstract
Immune activation plays a significant role in the disease progression of HIV. Microbial products, especially bacterial lipopolysaccharide (LPS), contribute to immune activation. Increasing evidence indicates that T lymphocyte homeostasis disruptions are associated with immune activation. However, the mechanism by which LPS affects disruption of immune response is still not fully understood. Chronically SHIVB’WHU-infected Chinese rhesus macaques received 50 μg/kg body weight LPS in this study. LPS administration affected the virus/host equilibrium by elevating the levels of viral replication and activating T lymphocytes. LPS induced upregulation of CD8+ naïve T cells and downregulated the number of CD4+ and CD8+ T effector memory cells. The downregulated effector memory cells are associated with a lower frequency of monofunctional and polyfunctional cells, and an upregulated programmed cell death-1 (PD-1) expression on CD4+ and CD8+ T cells was observed in monkeys after LPS stimulation. Our data provide new insights into the function of LPS in the immune activation in SHIV/HIV infection.
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- 2015
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47. Anti-HIV Activities and Mechanism of 12-O-Tricosanoylphorbol-20-acetate, a Novel Phorbol Ester from Ostodes katharinae
- Author
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Huan Chen, Rong Zhang, Rong-Hua Luo, Liu-Meng Yang, Rui-Rui Wang, Xiao-Jiang Hao, and Yong-Tang Zheng
- Subjects
antiviral agent ,12-O-tricosanoylphorbol-20-acetate ,HIV ,Vif ,APOBEC3G ,phorbol ester ,Organic chemistry ,QD241-441 - Abstract
APOBEC3G is a member of the human cytidine deaminase family that restricts Vif-deficient viruses by being packaged with progeny virions and inducing the G to A mutation during the synthesis of HIV-1 viral DNA when the progeny virus infects new cells. HIV-1 Vif protein resists the activity of A3G by mediating A3G degradation. Phorbol esters are plant-derived organic compounds belonging to the tigliane family of diterpenes and could activate the PKC pathway. In this study, we identified an inhibitor 12-O-tricosanoylphorbol-20-acetate (hop-8), a novel ester of phorbol which was isolated from Ostodes katharinae of the family Euphorbiaceae, that inhibited the replication of wild-type HIV-1 and HIV-2 strains and drug-resistant strains broadly both in C8166 cells and PBMCs with low cytotoxicity and the EC50 values ranged from 0.106 μM to 7.987 μM. One of the main mechanisms of hop-8 is to stimulate A3G expressing in HIV-1 producing cells and upregulate the A3G level in progeny virions, which results in reducing the infectivity of the progeny virus. This novel mechanism of hop-8 inhibition of HIV replication might represents a promising approach for developing new therapeutics for HIV infection.
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- 2017
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48. Azvudine, a novel nucleoside reverse transcriptase inhibitor showed good drug combination features and better inhibition on drug-resistant strains than lamivudine in vitro.
- Author
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Rui-Rui Wang, Qing-Hua Yang, Rong-Hua Luo, You-Mei Peng, Shao-Xing Dai, Xing-Jie Zhang, Huan Chen, Xue-Qing Cui, Ya-Juan Liu, Jing-Fei Huang, Jun-Biao Chang, and Yong-Tang Zheng
- Subjects
Medicine ,Science - Abstract
Azvudine is a novel nucleoside reverse transcriptase inhibitor with antiviral activity on human immunodeficiency virus, hepatitis B virus and hepatitis C virus. Here we reported the in vitro activity of azvudine against HIV-1 and HIV-2 when used alone or in combination with other antiretroviral drugs and its drug resistance features. Azvudine exerted highly potent inhibition on HIV-1 (EC(50)s ranging from 0.03 to 6.92 nM) and HIV-2 (EC(50)s ranging from 0.018 to 0.025 nM). It also showed synergism in combination with six approved anti-HIV drugs on both C8166 and PBMC. In combination assay, the concentrations of azvudine used were 1000 or 500 fold lower than other drugs. Azvudine also showed potent inhibition on NRTI-resistant strains (L74V and T69N). Although M184V caused 250 fold reduction in susceptibility, azvudine remained active at nanomolar range. In in vitro induced resistant assay, the frequency of M184I mutation increased with induction time which suggests M184I as the key mutation in azvudine treatment. As control, lamivudine treatment resulted in a higher frequency of M184I/V given the same induction time and higher occurrence of M184V was found. Molecular modeling analysis suggests that steric hindrance is more pronounced in mutant M184I than M184V due to the azido group of azvudine. The present data demonstrates the potential of azvudine as a complementary drug to current anti-HIV drugs. M184I should be the key mutation, however, azvudine still remains active on HIV-1LAI-M184V at nanomolar range.
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- 2014
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49. DB-02, a C-6-cyclohexylmethyl substituted pyrimidinone HIV-1 reverse transcriptase inhibitor with nanomolar activity, displays an improved sensitivity against K103N or Y181C than S-DABOs.
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Xing-Jie Zhang, Li-He Lu, Rui-Rui Wang, Yue-Ping Wang, Rong-Hua Luo, Christopher Cong Lai, Liu-Meng Yang, Yan-Ping He, and Yong-Tang Zheng
- Subjects
Medicine ,Science - Abstract
6-(cyclohexylmethyl)-5-ethyl-2-((2-oxo-2-phenylethyl)thio)pyrimidin-4(3H)-one (DB-02) is a member of the newly reported synthetic anti-HIV-1 compounds dihydro-aryl/alkylsulfanyl-cyclohexylmethyl-oxopyrimidines, S-DACOs. In vitro anti-HIV-1 activity and resistance profile studies have suggested that DB-02 has very low cytotoxicity (CC50>1mM) to cell lines and peripheral blood mononuclear cells (PBMCs). It displays potent anti-HIV-1 activity against laboratory adapted strains and primary isolated strains including different subtypes and tropism strains (EC50s range from 2.40 to 41.8 nM). Studies on site-directed mutagenesis, genotypic resistance profiles revealed that V106A was the major resistance contributor for the compound. Molecular docking analysis showed that DB-02 located in the hydrophobic pocket with interactions of Lys101, Val106, Leu234, His235. DB-02 also showed non-antagonistic effects to four approved antiretroviral drugs. All studies indicated that DB-02 would be a potential NNRTI with low cytotoxicity and improved activity.
- Published
- 2013
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50. Synthesis and Anti-HIV-1 Activity Evaluation for Novel 3a,6a-Dihydro-1H-pyrrolo[3,4-c]pyrazole-4,6-dione Derivatives
- Author
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Guan-Nan Liu, Rong-Hua Luo, Yu Zhou, Xing-Jie Zhang, Jian Li, Liu-Meng Yang, Yong-Tang Zheng, and Hong Liu
- Subjects
anti-HIV-1 ,integrase ,synthesis ,SAR ,AIDS ,Organic chemistry ,QD241-441 - Abstract
The search for new molecular constructs that resemble the critical two-metal binding pharmacophore and the halo-substituted phenyl functionality required for HIV-1 integrase (IN) inhibition represents a vibrant area of research within drug discovery. As reported herein, we have modified our recently disclosed 1-[2-(4-fluorophenyl)ethyl]-pyrrole-2,5-dione scaffolds to design 35 novel compounds with improved biological activities against HIV-1. These new compounds show single-digit micromolar antiviral potencies against HIV-1 and low toxicity. Among of them, compound 9g and 15i had potent anti-HIV-1 activities (EC50 < 5 μM) and excellent therapeutic index (TI, CC50/EC50 > 100). These two compounds have potential as lead compounds for further optimization into clinical anti-HIV-1 agents.
- Published
- 2016
- Full Text
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