Search

In this paper, an automatic connection method of virtual terminals based on the distance weight vector optimization model is proposed to realize the automatic connection of virtual terminals. The method defines the similarity of virtual terminal connections based on the edit distance, establishes an optimization model based on the sample data of virtual connections, and uses the particle swarm optimization to calculate the distance weight vector, so that the edit distance similarity can be adapted to the equipment produced by various manufacturers. Finally, the dummy terminals in the two pending IEDs (Intelligent Electronic Devices) are matched based on the similarity, and the matching reliability is given. The calculation example results show that this method can accurately realize the automatic connection of virtual terminals, effectively reduce the workload of substation construction, and improve the design quality of virtual terminals.

The CREB-regulated transcriptional co-activators (CRTCs), including CRTC1, CRTC2 and CRTC3, enhance transcription of CREB-targeted genes. In addition to regulating host gene expression in response to cAMP, CRTCs also increase the infection of several viruses. While human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR) promoter harbors a cAMP response element and activation of the cAMP pathway promotes HIV-1 transcription, it remains unknown whether CRTCs have any effect on HIV-1 transcription and HIV-1 infection. Here, we reported that CRTC2 expression was induced by HIV-1 infection, but CRTC2 suppressed HIV-1 infection and diminished viral RNA expression. Mechanistic studies revealed that CRTC2 inhibited transcription from HIV-1 LTR and diminished RNA Pol II occupancy at the LTR independent of its association with CREB. Importantly, CRTC2 inhibits the activation of latent HIV-1. Together, these data suggest that in response to HIV-1 infection, cells increase the expression of CRTC2 which inhibits HIV-1 gene expression and may play a role in driving HIV-1 into latency.

Schlafen-5 (SLFN5) is an interferon-induced protein of the Schlafen family, which are involved in immune responses and oncogenesis. To date, little is known regarding its anti-HIV-1 function. Here, the authors report that overexpression of SLFN5 inhibits HIV-1 replication and reduces viral mRNA levels, whereas depletion of endogenous SLFN5 promotes HIV-1 replication. Moreover, they show that SLFN5 markedly decreases the transcriptional activity of HIV-1 long terminal repeat (LTR) via binding to two sequences in the U5-R region, which consequently represses the recruitment of RNA polymerase II to the transcription initiation site. Mutagenesis studies show the importance of nuclear localization and the N-terminal 1–570 amino acids fragment in the inhibition of HIV-1. Further mechanistic studies demonstrate that SLFN5 interacts with components of the PRC2 complex, G9a and Histone H3, thereby promoting H3K27me2 and H3K27me3 modification leading to silencing HIV-1 transcription. In concert with this, they find that SLFN5 blocks the activation of latent HIV-1. Altogether, their findings demonstrate that SLFN5 is a transcriptional repressor of HIV-1 through epigenetic modulation and a potential determinant of HIV-1 latency.

Given the emerging pivotal roles of stimulator of interferon genes (STING) in host pathogen defense and immune-oncology, STING is regarded as a promising target for drug development. Cyclic dinucleotides (CDNs) are the first-generation STING agonists. However, their poor metabolic stability and membrane permeability limits their therapeutic application. In contrast, small-molecule STING agonists show superior properties such as molecular weight, polar character, and delivery diversity. The quest for a potent small-molecular agonist of human STING remains ongoing. In our study, through an IRF/IFN pathway-targeted cell-based screen of a natural products library, we identified a small-molecular STING agonist, Ziyuglycoside II, termed ST12, with potent stimulation of the IRF/IFN and NF-κB pathways. Furthermore, its binding to the C-terminal domain of human STING, detected by bio-layer interferometry, indicates that ST12 is a human STING agonist. Further Tanimoto similarity analysis with existing small-molecule STING agonists indicates that ST12 is a lead compound with a novel core structure for the further optimization.

By following up on the design vector of optimizing amine-based HIV-1 protease inhibitors, we have designed and biologically evaluated a novel class of inhibitors with the free nitrogen or sulphone in morpholine cores as P2 ligands in combination with diverse substituted phenylsulfonamide P2' ligands. As it turns out, a majority of these inhibitors exhibit prominent enzymatic inhibitory activity in low nanomolar ranges with relatively low cytotoxicity. Particularly, inhibitor 1e containing a morpholine carboxamide P2 ligand and a 4-hydroxyphenylsulfonamide P2' ligand illustrates a robust enzyme inhibitory IC

Adjectives are common in natural language, and their usage and semantics have been studied broadly. In recent years, with the rapid growth of knowledge bases (KBs), many knowledge-based question answering (KBQA) systems are developed to answer users’ natural language questions over KBs. A fundamental task of such systems is to transform natural language questions into structural queries, e.g., SPARQL queries. Thus, such systems require knowledge about how natural language expressions are represented in KBs, including adjectives. In this paper, we specifically address the problem of representing adjectives over KBs. We propose a novel approach, called Adj2SP, to represent adjectives as SPARQL query patterns. Adj2SP contains a statistic-based approach and a neural network-based approach, both of them can effectively reduce the search space for adjective representations and overcome the lexical gap between input adjectives and their target representations. Two adjective representation datasets are built for evaluation, with adjectives used in QALD and Yahoo! Answers, as well as their representations over DBpedia. Experimental results show that Adj2SP can generate representations of high quality and significantly outperform several alternative approaches in F1-score. Furthermore, we publish Lark, a lexicon for adjective representations over KBs. Current KBQA systems show an improvement of over 24% in F1-score by integrating Adj2SP.

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.

Human APOBEC3G (hA3G) is a cytidine deaminase which inhibits HIV-1 replication. The HIV-1 accessory protein viral infectivity factor (Vif) counteracts with hA3G by targeting it for proteasomal degradation. In this work, we constructed and optimized molecular models of the hA3G dimer and the hA3G–Vif complex. The molecular modeling study revealed that the loop7 motif of hA3G appears on the interfaces of both the hA3G–Vif complex and the hA3G dimer. Biochemical analysis provided evidence suggesting that binding of Vif to hA3G results in steric blocking of hA3G dimerization, implying that monomeric hA3G serves as a substrate for Vif-mediated degradation. Furthermore, we presented evidence for the important roles of the loop7 motif, especially the central residues within the region, in hA3G dimerization, hA3G--Vif interaction, Vif-mediated hA3G degradation as well as subcellular localization of hA3G. This work highlights a multiple-task interface formed by loop7 motif, which regulates biological function of hA3G, thus providing the feasibility of the strategy of blocking Vif-mediated A3G degradation by targeting the putative site around loop7., Graphical abstract The molecular modeling study revealed that the loop7 motif of hA3G appears on the interfaces of both the hA3G–Vif complex and the hA3G dimer, and the biochemical analysis provided evidence supporting that binding of Vif to hA3G results in steric blocking of hA3G dimerization.fx1

Formal query generation aims to generate correct executable queries for question answering over knowledge bases (KBs), given entity and relation linking results. Current approaches build universal paraphrasing or ranking models for the whole questions, which are likely to fail in generating queries for complex, long-tail questions. In this paper, we propose SubQG, a new query generation approach based on frequent query substructures, which helps rank the existing (but nonsignificant) query structures or build new query structures. Our experiments on two benchmark datasets show that our approach significantly outperforms the existing ones, especially for complex questions. Also, it achieves promising performance with limited training data and noisy entity/relation linking results., Accepted by the 2019 Conference on Empirical Methods in Natural Language Processing (EMNLP 2019)

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.

Ethnopharmacological relevance Artemisia scoparia Waldst.et Kit (A. scoparia), is an important medicinal plant mainly distributed in China, Korea, Japan, Pakistan, India, Central Europe, Saudi Arabia and Iran. It has been used for a long history to treat fever, inflammation, jaundice, and infection, but systematic reviews about the medicinal uses of A. scoparia are still lacking. Aim of the study This review is to provide up-to-date information on A. scoparia, including its botanical characteristics, medicinal resources, traditional uses, phytochemistry and pharmacological effects, in exploring therapeutic and scientific potentials. Materials and methods The information related to this article was systematically collected from the scientific literature databases including PubMed, Google Scholar, Web of Science, Science Direct, Springer, China National Knowledge Infrastructure, local books, PhD and MS dissertations, and other web sources. Results Herein a total of 102 compounds, such as flavonoids, coumarins, chromones, steroids, volatile oil and phenolic acid isolated from A. scoparia are summarized. Among these compounds, the effects of flavonoids, coumarins and phenolic acids were extensively studied. We have comprehensively summarized modern pharmacological studies on A. scoparia and demonstrated A. scoparia and its active components have a wide range of pharmaceutical activities, such as anticancer, anti-inflammatory, antibacterial, liver protection, antiatherogenic, antiviral as well as neuroprotective functions. Conclusions As an important Chinese medicinal plant, modern pharmacological studies have demonstrated that A. scoparia has diverse bioactivities, especially on liver protection and anti-inflammatory activities. These prominent bioactivities highlight prospects on new drug development. Nevertheless, the comprehensive evaluation, long-term in vivo toxicity, and clinical efficacy of A. scoparia require further in-depth research.

Assembly and budding of human immunodeficiency virus type 1 (HIV-1) particles is a complex process involving a number of host proteins. We have previously reported that the RhoA effector citron kinase enhances HIV-1 production. However, the underlying mechanism is not clear. In this study, we found that citron kinase interacted with HIV-1 Gag protein via its zinc finger and leucine zipper domains. Electron microscopy analysis revealed that citron kinase induced viral particle assembly in multivesicular bodies (MVBs). Citron kinase enhanced ubiquitination of HIV-1 Gag protein. Knockdown of Nedd4L, a member of the HECT ubiquitin E3 ligase family, partly decreased the ability of citron kinase to enhance HIV-1 production and reduced ubiquitination of HIV-1 Gag. Interestingly, the function of citron kinase to promote HIV-1 budding was severely impaired when endogenous ALIX was knocked down. Overexpression of the AAA-type ATPase VPS4 eliminated citron-kinase-mediated enhancement of HIV-1 production. Our results suggest that citron kinase interacts with HIV-1 Gag and enhances HIV-1 production by promoting Gag ubiquitination and inducing viral release via the MVB pathway.

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.

Answering questions in Gaokao (the national college entrance examination in China) brings a great challenge for recent AI systems, where the difficulty of questions and the lack of formal knowledge are two main obstacles, among others. In this paper, we focus on answering multiple-choice questions in geographical Gaokao. Specifically, a concept graph is automatically constructed from textbook tables and Chinese wiki encyclopedia, to capture core concepts and relations in geography. Based on this concept graph, a graph search based question answering approach is designed to find explainable inference paths between questions and options. We developed an online system called CGQA and conducted experiments on two real datasets created from the last ten year geographical Gaokao. Our experimental results demonstrated that CGQA can generate accurate judgments and provide explainable solving procedures. Additionally, CGQA showed promising improvement by combining with existing approaches.

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.

Additional file 1: Figure S1. 2-thio-6-azauridine inhibits Vpu-mediated down-regulation of cell surface BST-2 (FACS). HeLa-Vpu and HeLa cells were treated with increasing concentrations of 2-thio-6-azauridine (0.05 µM、0.5 µM、5 µM) for 24 h. Cell surface BST-2 was measured using flow cytometry.

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.

Human immunodeficiency virus (HIV)-1 infection changes transcriptional profiles and regulates. the factors and machinery of the host that facilitate viral replication. Our previous study suggested that the serine/threonine kinase citron kinase (citK) promotes HIV-1 egress. To ascertain if HIV-1 infection affects citK expression in primary cells, peripheral blood mononuclear cells were infected with vesicular stomatitis virus G protein (VSV-G)-pseudotyped HIV-1 vector NL4-3-luc viruses, which resulted in remarkably increased expression of citK. citK overexpression led to a more than two-fold increase in HIV-1 production, whereas a significant decrease was observed when citK was depleted in CD4+ T cells. Infection with HIV-1 pseudoviruses induced increases in the mRNA and protein levels of citK by 2. 5- and 2. 7-fold in HEK293T cells, respectively. By cloning the 5-kb promoter of citK into a luciferase reporter system and transfecting the construct into HEK293T cells, enhanced luciferase activity was observed during HIV-1 infection. Taken together, these data demonstrate that HIV-1 infection upregulates citK expression at the transcriptional level, and thereby renders the host more susceptible to invasion by HIV-1.

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.

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.

Hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) is a key component of the endosomal sorting complexes required for transport and has been demonstrated to play a regulatory role in endocytosis/exocytosis and the accumulation of internal vesicles in multivesicular bodies. Citron kinase is a Ser/The kinase that we previously reported to enhance human immunodeficiency virus type 1 (HIV-1) virion production. However, the relationship between Hrs and citron kinase in HIV-1 production remains elusive. Here, we report that Hrs interacts with citron kinase via its FYVE domain. Overexpression of Hrs or the FYVE domain resulted in a significant decrease in HIV-1 virion production. Depletion of Hrs by RNA interference in HEK293T cells increased HIV-1 virion production and enhanced the activity of citron kinase. These data suggest that Hrs inhibits HIV-1 production by inhibiting citron kinase-mediated exocytosis.