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Summary: Long noncoding RNAs (lncRNAs) participate in host antiviral defense by modulating immune responses. However, it remains largely unexplored how viruses exploit interferon (IFN)-independent host lncRNAs to facilitate viral replication. Here, we have identified a group of human lncRNAs that modulate influenza A virus (IAV) replication in a loss-of-function screen and found that an IFN-independent lncRNA, called IPAN, is hijacked by IAV to assist IAV replication. IPAN is specifically induced by IAV infection independently of IFN and associates with and stabilizes viral RNA-dependent RNA polymerase PB1, enabling efficient viral RNA synthesis. Silencing IPAN results in PB1 degradation and severely impairs viral infection. Therefore, our data unveil an important role of host lncRNAs in promoting viral replication by modulating viral protein stability. Our findings may open avenues to the development of antiviral therapeutics. : Wang et al. report that influenza A virus hijacks a human long noncoding RNA IPAN to stabilize viral RNA polymerase PB1, enabling efficient viral RNA synthesis. They unveil an important role of host noncoding RNAs in promoting viral replication by modulating viral protein stability. Keywords: lncRNA, influenza A virus, IPAN, PB1, degradation, hijack, RdRp, interferon, viral replication

Mounting evidence indicates that Zika virus (ZIKV) is closely related to neurological disorders such as microcephaly and Guillain-Barre syndrome. There are currently no effective vaccines and FDA-approved inhibitors against ZIKV infection. The flaviviral heterodimeric serine protease NS2B-NS3 plays an essential role in ZIKV maturation and replication, thus becoming a promising target in anti-ZIKV therapy. Herein, we developed a fluorescence-based screening assay to search for inhibitors targeting the ZIKV NS2B-NS3 protease (ZIKVpro), and identified theaflavin-3,3'-digallate (ZP10), a natural active compound derived from black tea, as a potent ZIKV protease inhibitor in vitro (IC50 = 2.3 μM). ZP10 exhibited dose-dependent inhibitory effect on ZIKV replication (EC50 = 7.65 μM). Western blot analysis suggested that ZP10 inhibited the cleavage processing of viral polyprotein precursor in cells either infected with ZIKV or expressing minimal self-cleaving proteinase NS2B-3 protease, resulting in inhibition of virus growth. Moreover, ZP10 was showed to directly bind to ZIKVpro, and a docking model further revealed that ZP10 interacted with several critical residues at the proteolytic cavity of the ZIKVpro. This study highlights that ZP10 has anti-ZIKV potency through ZIKVpro inhibition, which indicates its potential application in anti-ZIKV therapy.

Ethnopharmacological relevance Coreopsis tinctoria Nutt. (family Asteraceae) is an important traditional medicine in North America, Europe, and Asia for quite a long historical period, which has received great attention due to its health-benefiting activities, including disinfection, treatment sexual infection, diarrhoea, acute and chronic dysentery, red-eye swelling as well as pain, heat, thirst, hypertension, palpitation, gastrointestinal discomfort, and loss of appetite. Aim of the review The purpose of this review is to give an overview of the current phytochemistry and pharmacological activities of C. tinctoria, and reveals the correlation among its traditional uses, phytochemistry, pharmacological profile, and potential toxicity. Materials and methods This review is based on published studies and books from electronic sources and library, including the online ethnobotanical database, ethnobotanical monographs, Scopus, SciFinder, Baidu Scholar, CNKI, and PubMed. These reports are related to the traditional uses, phytochemistry, pharmacology, and toxicology of C. tinctoria. Results Coreopsis tinctoria is traditionally used in diarrhoea, infection, and chronic metabolic diseases. From 1954 to now, more than 120 chemical constituents have been identified from C. tinctoria, such as flavonoids, polyacetylenes, polysaccharides, phenylpropanoids, and volatile oils. Flavonoids are the major bioactive components in C. tinctoria. Current research has shown that its extracts and compounds possess diverse biological and pharmacological activities such as antidiabetes, anti-cardiovascular diseases, antioxidant, anti-inflammatory, protective effects on organs, neuroprotective effects, antimicrobial, and antineoplastic. Studies in animal models, including acute toxicity, long-term toxicity, and genotoxicity have demonstrated that Snow Chrysanthemum is a non-toxic herb, especially for its water-soluble parts. Conclusions Recent findings regarding the main phytochemical and pharmacological properties of C. tinctorial have confirmed its traditional uses in anti-infection and treatment of chronic metabolic disease and, more importantly, have revealed the plant as a valuable medicinal plant resource for the treatment of a wide range of diseases. The available reports indicated that most of the bioactivities in C. tinctorial could be attributed to flavonoids. However, higher quality studies on animals and humans studies are required to explore the efficacy and mechanism of action of C. tinctoria in future.

Background Despite that most HIV-infected individuals experience progressive CD4+ T cell loss and develop AIDS, a minority of HIV-infected individuals remain asymptomatic and maintain high level CD4+ T cell counts several years after seroconversion. Efforts have been made to understand the determinants of the nonprogressive status, exemplified by the clinical course of elite controllers (ECs) who maintain an undetectable viremia and viremic nonprogressors (VNPs) who have a normal CD4+ count in spite of circulating viral load. However, the intrinsic mechanism underlying nonprogression remained elusive. In this study, we performed an integrative analysis of transcriptional profiles to pinpoint the underlying mechanism for a naturally occurring viral control. Methods Three microarray datasets, reporting mRNA expression of the LTNPs or ECs in HIV-infected patients, were retrieved from Gene Expression Ominbus (GEO) or Arrayexpress databases. These datasets, profiled on the same type of microarray chip, were selected and merged by a bioinformatic approach to build a meta-analysis derived transcriptome (MADNT). In addition, we investigated the different transcriptional pathways and potential biomarkers in CD4+ and CD8+ cells in ECs and whole blood in VNPs compared to HIV progressors. The combined transcriptome and each subgroup was subject to gene set enrichment analysis and weighted co-expression network analysis to search potential transcription patterns related to the non-progressive status. Results 30 up-regulated genes and 83 down-regulated genes were identified in lymphocytes from integrative meta-analysis of expression data. The interferon response and innate immune activation was reduced in both CD4+ and CD8+ T cells from ECs. Several characteristic genes including CMPK1, CBX7, EIF3L, EIF4A and ZNF395 were indicated to be highly correlated with viremic control. Besides that, we indicated that the reduction of ribosome components and blockade of translation facilitated AIDS disease progression. Most interestingly, among VNPs who have a relatively high viral load, we detected a two gene-interaction networks which showed a strong correlation to immune control even with a rigorous statistical threshold (p value = 2−e4 and p value = 0.004, respectively) by WGCNA. Conclusions We have identified differentially expressed genes and transcriptional patterns in ECs and VNPs compared to normal chronic HIV-infected individuals. Our study provides new insights into the pathogenesis of HIV and AIDS and clues for the therapeutic strategies for anti-retroviral administration. Electronic supplementary material The online version of this article (10.1186/s12967-019-1777-7) contains supplementary material, which is available to authorized users.

The interaction of programmed death-1 (PD-1) and it's ligands (PD-L1) is an important immune checkpoint and blockade of PD-1/PD-L1 axis with antibodies against PD-L1 showed promising anti-tumor activity in clinical practice. However, only a small percentage of patients can benefit from PD-L1 mAbs. Small molecular kinase inhibitors have been widely used as antitumor drugs for many years, and several kinase inhibitors were recently reported to inhibit the expression of PD-L1. However, the connections between PD-L1 expression and kinase inhibitors were not thoroughly elucidated. Herein, we set up a novel and robust screening system to identify small molecular compounds which downregulate the PD-L1 level of tumor cell based on Odyssey on/in cell quantitative immunoblots technology. A collected kinase inhibitor library was screened and 14 hits were further confirmed by western blot and flow cytometry. System biological analysis and further bio-assay identified a synergy combination between KU-60019 and Vacquinol-1 in downregulation of PD-L1. Taken together, the work established a novel method to screen the PD-L1 down-regulators using kinase inhibitors library, thus providing new clues for the application of kinase inhibitors in cancer immunotherapy.

OBJECTIVES Genetic polymorphism of viral receptors is relevant to risks of HIV-1 infection, while it is still under debated whether the polymorphism of SDF1, a unique ligand for HIV-1 coreceptor CXCR4, is associated with HIV susceptibility and AIDS disease progression. Therefore, we provided an updated quantitative assessment by meta-analysis from 16 case-control and 7 cohort studies. METHODS Articles reporting the relationship between SDF1 polymorphism and HIV susceptibility or AIDS progression were retrieved from PubMed, Embase and Ovid electronic databases up to Apr 2017. Data were pooled by odds ratios (ORs) for HIV-1 infection with 95% confidence intervals (CIs) and summary relative hazards (RHs) for AIDS progression with 95% CIs using 1987 Center for Disease Control (CDC) case definition of AIDS (CDC87) and 1993 Center for Disease Control (CDC) case definition of AIDS (CDC93) and death as endpoints. RESULTS As a result, 16 studies regarding susceptibility to HIV-1 infection with 2803 HIV-infected patients and 3697 healthy individuals and 7 studies regarding disease progression with 4239 subjects were included in the meta-analysis. For risks of infection, no evidences indicated SDF1 polymorphism was associated with the risk of HIV-1 infection in all genetic models (recessive model: OR = 0.94, 95% Cl: 0.75-1.17; homozygous model: OR = 0.89, 95% Cl: 0.70-1.15; heterozygous model: OR = 1.06, 95% Cl: 0.83-1.35; allele model: OR = 0.95, 95% Cl: 0.79-1.13), Furthermore, we failed to find an delayed AIDS progression except in some specific cohorts including MACS cohorts (RH = 0.38, 95% Cl: 0.17-0.59 for time to AIDS; RH = 0.27, 95% Cl: 0.07-0.46 for time to death at the study entry). CONCLUSIONS Overall, no significant association was found between SDF1 polymorphism and HIV susceptibility. A protective effect of SDF1 on AIDS progression and death was seen especially in two studies based on the same cohorts. In conclusion, SDF1 polymorphism exerts a moderate protective effect against AIDS disease deterioration in some specific populations.

Bone marrow stromal cell antigen 2 (BST-2) inhibits the release of HIV-1 and other enveloped viruses from the cell surface. HIV-1 Vpu binds to BST-2 through an interaction between transmembrane domains (TMD) of the two proteins and induces the downregulation of cell surface BST-2, thereby counteracting its antiviral activity. In this study, we designed and prepared a modified peptide BST2-TM-P1, which include the sequence of BST-2 TMD, keeping its property competing with BST-2 to bind with Vpu. Biological assay results indicate BST2-TM-P1 could increase the BST-2 level at the cell surface in Vpu dependent manner and significantly inhibit the replication of HIV-1 virion. Our studies indicate that blocking the interaction of Vpu and BST-2 is an effective way to combat HIV-1 infection. © 2014 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 102: 280–287, 2014.

APOBEC3G(A3G) is a host cytidine deaminase that incorporates into HIV-1 virions and efficiently inhibits viral replication. The virally encoded protein Vif binds to A3G and induces its degradation, thereby counteracting the antiviral activity of A3G. Vif-mediated A3G degradation clearly represents a potential target for anti-HIV drug development. Currently, there is an urgent need for understanding the three dimensional structure of full-length A3G. In this work, we use a homology modeling approach to propose a structure for A3G based on the crystal structure of APOBEC2 (APO2) and the catalytic domain structure of A3G. Two compounds, IMB26 and IMB35, which have been shown to bind to A3G and block degradation by Vif, were docked into the A3G model and the binding modes were generated for further analysis. The results may be used to design or optimize molecules targeting Vif–A3G interaction, and lead to the development of novel anti-HIV drugs.

Human BST-2 inhibits HIV-1 replication by tethering nascent virions to the cell surface. HIV-1 codes Vpu that counteracts BST-2 by down-regulating this restriction factor from the cell surface. This important function makes Vpu a potential therapeutic target. Yet, no agents have been reported to block Vpu from antagonizing BST-2. In this study, we report a small molecule compound IMB-LA that abrogates the function of Vpu and thereby strongly suppresses HIV-1 replication by sensitizing the virus to BST-2 restriction. Further studies revealed that IMB-LA specifically inhibits Vpu-mediated degradation of BST-2 and restores the expression of BST-2 at the cell surface. Although IMB-LA does not prevent Vpu from interacting with BST-2 or β-TrCP2-containing ubiquitin E3 ligase, sorting of BST-2 into lysosomes in Vpu-expressing cells is blocked by IMB-LA. Most importantly, HIV-1 release and infection is inhibited by IMB-LA only in BST-2-expressing cells. In summary, results herein demonstrated that IMB-LA could specifically inhibit the degradation of BST-2 induced by Vpu and impair HIV-1 replication in a BST-2 dependent manner, suggesting the feasibility of utilizing small molecule compounds to disable the antagonist function of Vpu and thereby expose HIV-1 to the restriction by BST-2.

Backgroud BST-2 is an interferon-induced host restriction factor that inhibits the release of diverse mammalian enveloped viruses from infected cells by physically trapping the newly formed virions onto the host cell surface. Human Immunodeficiency Virus-1 (HIV-1) encodes an accessory protein Vpu that antagonizes BST-2 by down-regulating BST-2 from the cell surface. Results Using a cell-based ELISA screening system, we have discovered a lead compound, 2-thio-6-azauridine, that restores cell surface BST-2 level in the presence of Vpu. This compound has no effect on the expression of BST-2 and Vpu, but inhibits Vpu-mediated BST-2 down-regulation and exerts no effect on Vpu-induced down-regulation of CD4 or KSHV K5 protein induced BST-2 down-regulation. 2-thio-6-azauridine suppresses HIV-1 production in a BST-2-dependent manner. Further results indicate that 2-thio-6-azauridine does not interrupt the interaction of BST-2 with Vpu and β-TrCP2, but decreases BST-2 ubiquitination. Conclusion Our study demonstrates the feasibility of using small molecules to target Vpu function and sensitize wild type HIV-1 to BST-2-mediated host restriction. Electronic supplementary material The online version of this article (doi:10.1186/s12977-016-0247-z) contains supplementary material, which is available to authorized users.

While Highly Active Antiretroviral Therapy (HAART) has significantly decreased the mortality of human immunodeficiency virus (HIV)-infected patients, emerging drug resistance to approved HIV-1 integrase inhibitors highlights the need to develop new antivirals with novel mechanisms of action. In this study, we screened a library of microbial natural compounds from endophytic fungus Colletotrichum sp. and identified alternariol 5-O-methyl ether (AME) as a compound that inhibits HIV-1 pre-integration steps. Time-of addition analysis, quantitative real-time PCR, confocal microscopy, and WT viral replication assay were used to elucidate the mechanism. As opposed to the approved integrase inhibitor Raltegravir, AME reduced both the integrated viral DNA and the 2-long terminal repeat (2-LTR) circular DNA, which suggests that AME impairs the nuclear import of viral DNA. Further confocal microscopy studies showed that AME specifically blocks the nuclear import of HIV-1 integrase and pre-integration complex without any adverse effects on the importin α/β and importin β-mediated nuclear import pathway in general. Importantly, AME inhibited Raltegravir-resistant HIV-1 strains and exhibited a broad anti-HIV-1 activity in diverse cell lines. These data collectively demonstrate the potential of AME for further development into a new HIV inhibitor, and suggest the utility of viral DNA nuclear import as a target for anti-HIV drug discovery.