Journal of Microbiology

Review

The Role of Extracellular Vesicles in Pandemic Viral Infections.: Woosung Shim, Anjae Lee, Jung-Hyun Lee; J. Microbiol. 2024;62(6):419-427. Published online June 25, 2024; DOI: https://doi.org/10.1007/s12275-024-00144-x

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Abstract: Extracellular vesicles (EVs), of diverse origin and content, are membranous structures secreted by a broad range of cell types. Recent advances in molecular biology have highlighted the pivotal role of EVs in mediating intercellular communication, facilitated by their ability to transport a diverse range of biomolecules, including proteins, lipids, DNA, RNA and metabolites. A striking feature of EVs is their ability to exert dual effects during viral infections, involving both proviral and antiviral effects. This review explores the dual roles of EVs, particularly in the context of pandemic viruses such as HIV-1 and SARS-CoV-2. On the one hand, EVs can enhance viral replication and exacerbate pathogenesis by transferring viral components to susceptible cells. On the other hand, they have intrinsic antiviral properties, including activation of immune responses and direct inhibition of viral infection. By exploring these contrasting functions, our review emphasizes the complexity of EV-mediated interactions in viral pathogenesis and highlights their potential as targets for therapeutic intervention. The insights obtained from investigating EVs in the context of HIV-1 and SARS-CoV-2 provide a deeper understanding of viral mechanisms and pathologies, and offer a new perspective on managing and mitigating the impact of these global health challenges.

Journal Article

Structural insights into the psychrophilic germinal protease PaGPR and its autoinhibitory loop: Chang Woo Lee , Saeyoung Lee , Chang-Sook Jeong , Jisub Hwang , Jeong Ho Chang , In-Geol Choi , T. Doohun Kim , HaJeung Park , Hye-Yeon Kim , Jun Hyuck Lee; J. Microbiol. 2020;58(9):772-779. Published online September 1, 2020; DOI: https://doi.org/10.1007/s12275-020-0292-0

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2 Citations

Abstract: In spore forming microbes, germination protease (GPR) plays a key role in the initiation of the germination process. A critical step during germination is the degradation of small acidsoluble proteins (SASPs), which protect spore DNA from external stresses (UV, heat, low temperature, etc.). Inactive zymogen GPR can be activated by autoprocessing of the N-terminal pro-sequence domain. Activated GPR initiates the degradation of SASPs; however, the detailed mechanisms underlying the activation, catalysis, regulation, and substrate recognition of GPR remain elusive. In this study, we determined the crystal structure of GPR from Paenisporosarcina sp. TG-20 (PaGPR) in its inactive form at a resolution of 2.5 Å. Structural analysis showed that the active site of PaGPR is sterically occluded by an inhibitory loop region (residues 202–216). The N-terminal region interacts directly with the self-inhibitory loop region, suggesting that the removal of the N-terminal pro-sequence induces conformational changes, which lead to the release of the self-inhibitory loop region from the active site. In addition, comparative sequence and structural analyses revealed that PaGPR contains two highly conserved Asp residues (D123 and D182) in the active site, similar to the putative aspartic acid protease GPR from Bacillus megaterium. The catalytic domain structure of PaGPR also shares similarities with the sequentially non-homologous proteins HycI and HybD. HycI and HybD are metalloproteases that also contain two Asp (or Glu) residues in their active site, playing a role in metal binding. In summary, our
results
provide useful insights into the activation process of PaGPR and its active conformation.

Research Support, Non-U.S. Gov'ts

From the traditional Chinese medicine plant Schisandra chinensis new scaffolds effective on HIV-1 reverse transcriptase resistant to non-nucleoside inhibitors: Lijia Xu , Nicole Grandi , Claudia Del Vecchio , Daniela Mandas , Angela Corona , Dario Piano , Francesca Esposito , Cristina Parolin , Enzo Tramontano; J. Microbiol. 2015;53(4):288-293. Published online March 4, 2015; DOI: https://doi.org/10.1007/s12275-015-4652-0

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62 Citations

Abstract: HIV-1 reverse transcriptase (RT) is still an extremely attractive pharmaceutical target for the identification of new inhibitors possibly active on drug resistant strains. Medicinal plants are a rich source of chemical diversity and can be used to identify novel scaffolds to be further developed by chemical modifications. We investigated the ability of the main lignans from Schisandra chinensis (Turcz.) Baill. fruits, commonly used in Traditional Chinese Medicine, to affect HIV-1 RT functions. We purified 6 lignans from Schisandra chinensis fruits and assayed their effects on HIV-1 RT and viral replication. Among the S. chinensis fruit lignans, Schisandrin B and Deoxyschizandrin selectively inhibited the HIV-1 RTassociated DNA polymerase activity. Structure activity relationship revealed the importance of cyclooctadiene ring substituents for efficacy. In addition, Schisandrin B was also able to impair HIV-1 RT drug resistant mutants and the early phases of viral replication. We identified Schisandrin B and Deoxyschizandrin as new scaffold for the further development of novel HIV-1 RT inhibitors.

NOTE] Envelope Diversity, Characteristics of V3 Region and Predicted Co-Receptor Usage of Human Immunodeficiency Viruses Infecting North Indians: Raiees Andrabi , Rajesh Kumar , Manju Bala , Ambili Nair , Prakash SS , Vandana Kushwaha , Kalpana Luthra; J. Microbiol. 2012;50(5):869-873. Published online November 4, 2012; DOI: https://doi.org/10.1007/s12275-012-2136-z

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9 Citations

Abstract: Subtypes of human immunodeficiency virus type 1 circulating in 21 north Indian patients were characterized based on the partial sequence of the gp120 envelope protein. A majority of viruses (85.7%, 18/21) were subtype C, while 14.3% (3/21) were subtype A. Sequence analysis revealed that the V3 region was highly conserved compared with V4 and V5. The predicted use of co-receptors indicated exclusive usage of R5, except for two subtype A viruses (AIIMS279 and AIIMS281). Our results demonstrate conservation within the V3 loop of subtype C viruses, and suggest the emergence of non-clade C viruses in the north Indian population.

Neutralization Potential of the Plasma of HIV-1 Infected Indian Patients in the Context of Anti-V3 Antibody Content and Antiretroviral Theraphy: Alok Kumar Choudhary , Raiees Andrabi , Somi Sankaran Prakash , Rajesh Kumar , Shubhasree Dutta Choudhury Choudhury , Naveet Wig , Ashutosh Biswas , Anjali Hazarika , Kalpana Luthra; J. Microbiol. 2012;50(1):149-154. Published online February 27, 2012; DOI: https://doi.org/10.1007/s12275-012-1246-y

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8 Citations

Abstract: We assessed the anti-V3 antibody content and viral neutralization potential of the plasma of 63 HIV-1-infected patients (antiretroviral naïve=39, treated=24) against four primary isolates (PIs) of clade C and a tier 1 clade B isolate SF162. Depletion and inhibition of anti-V3 antibodies in the plasma of five patients with high titers of anti-V3 antibodies led to modest change in the neutralization percentage against two PIs (range 0–21%). The plasma of antiretroviral-treated patients exhibited higher neutralization potential than that of the drug-naïve plasmas against the four PIs tested which was further evidenced by a follow-up study.

Anti-HIV-1 Efficacy of Extracts from Medicinal Plants: Su-A Lee , Seong-Karp Hong , Chang-Il Suh , Mi-Hwa Oh , Jeong-Ho Park , Byoung-Wook Choi , Seung-Won Park , Soon-Young Paik; J. Microbiol. 2010;48(2):249-252. Published online May 1, 2010; DOI: https://doi.org/10.1007/s12275-009-0176-9

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20 Citations

Abstract: The anti-HIV-1 activities of butanol, hexane, chloroform and water extracts from four widely used folk medicinal plants (Sophora flavescens, Tulipa edulis, Herba ephedra, and Pachyma hoelen Rumph) were evaluated in this study. The hexane extract of Pachyma hoelen Rumph, PH-4, showed effective inhibition against HIV-1. The 50% effective concentration (EC50) of PH-4 was 37.3 μg/ml in the p24 antigen assay and 36.8% in the HIV-1 recombinant RT activity test (at 200 μg/ml). In addition, the PH-4 showed the protective effect on the infected MT-4 cells, with a 58.2% rate of protection. The 50% cytotoxic concentration (CC50) of PH-4 was 100.6 μg/ml. These results suggest that PH-4 from Pachyma hoelen Rumph might be the candidate for the chemotherapy agent against HIV-1 infection with further study.

Timing and Evolution of the Most Recent Common Ancestor of the Korean Clade HIV Subtype B Based on Nef and Vif Sequences: Mi-Suk Kim , So-Young Jang , Chan-Seung Park , Keon-Myung Lee , Dong-Hun Lee , Chan-Hee Lee; J. Microbiol. 2009;47(1):85-90. Published online February 20, 2009; DOI: https://doi.org/10.1007/s12275-008-0240-x

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5 Citations

Abstract: Molecular phylogenetic studies of the HIV-1 isolated from Koreans have suggested the presence of the so- called “Korean clade”, which can be defined as a cluster free of foreign isolates. The Korean clade accounts for more than 60% of Korean isolates and exerts characteristic amino acid sequences. Thus, it is merited to estimate when this Korean clade first emerged in order to understand the evolutionary pattern of the Korean clade. We analyzed and reconstructed the most recent common ancestor (MRCA) sequences from nef (n=229) and vif (n=179) Korean clade sequences. Linear regression analyses of sequence divergence estimates were plotted against sampling years to infer the year in which there was zero divergence from the MRCA sequences. MRCA sequences suggested the Korean clade was first emerged around 1984, before the first detection of HIV-1 in Korea in 1985. Further studies on synonymous and nonsynonymous substitution rates suggested positive selection event for the Korean clade, while other subtype B had undergone negative to neutral evolution.

Improved Prediction of Coreceptor Usage and Phenotype of HIV-1 Based on Combined Features of V3 Loop Sequence Using Random Forest: Shungao Xu , Xinxiang Huang , Huaxi Xu , Chiyu Zhang; J. Microbiol. 2007;45(5):441-446.; DOI: https://doi.org/2592 [pii]

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Abstract: HIV-1 coreceptor usage and phenotype mainly determined by V3 loop are associated with the disease progression of AIDS. Predicting HIV-1 coreceptor usage and phenotype facilitates the monitoring of R5-to-X4 switch and treatment decision-making. In this study, we employed random forest to predict HIV-1 biological phenotype, based on 37 random features of V3 loop. In comparison with PSSM method, our RF predictor obtained higher prediction accuracy (95.1% for coreceptor usage and 92.1% for phenotype), especially for non-B non-C HIV-1 subtypes (96.6% for coreceptor usage and 95.3% for phenotype). The net charge, polarity of V3 loop and five V3 sites are seven most important features for predicting HIV-1 coreceptor usage or phenotype. Among these features, V3 polarity and four V3 sites (22, 12, 18 and 13) are first reported to have high contribution to HIV-1 biological phenotype prediction.

Analysis of Substitution Events in HIV-1 vif Gene of the Korean Clade: Chan Seung Park , Mi Sook Kim , Hyun Ah Yi , Dong Hun Lee , Keon Myung Lee , Chan Hee Lee; J. Microbiol. 2007;45(1):75-78.; DOI: https://doi.org/2487 [pii]

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Abstract: Nucleotide and amino acid substitution pattern in vif gene of the Korean clade of HIV-1 isolated from Koreans were analyzed using consensus sequences. At nucleotide level, transition/transversion substitution ratio was 1.88, and nonsynonymous/synonymous substitution ratio was 2.67, suggesting a divergent <br>evolution in the Korean clade. At amino acid level, there were 17 substitutions and G→E substitution at position 37 may be responsible for change in predicted secondary structure.

Molecular Phylogenetic Analysis of HIV-1 vif Gene from Korean Isolates: Chan Seung Park , Mi Sook Kim , Sung Duk Lee , Sung Soo Kim , Keon Myung Lee , Chan-Hee Lee; J. Microbiol. 2006;44(6):655-659.; DOI: https://doi.org/2461 [pii]

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Abstract: Phylogenetic studies of nef, pol, and env gene sequences of HIV-1 isolated from Koreans suggested the presence of a Korean clade in which Korean sequences are clustered to the exclusion of foreign sequences. We attempted to identify and characterize the Korean clade using all vif gene sequences isolated from Koreans registered in the NCBI GenBank database (n = 233). Most (77%) of the Korean isolates belonged to the Korean clade as a large subcluster in subtype B, designated the Korean clade subtype B (KCB). KCB sequences were relatively homogenous compared to Korean subtype B sequences that did not belong to the KCB (non-Korean clade subtype B; NKCB). Comparison of amino acid frequencies of KCB and NKCB sequences revealed several positions where the amino acid frequencies were significantly different. These amino acid residues were critical in separating KCB from NKCB or from foreign sequences, since substitution of these amino acids in KCB with the NKCB amino acids relocated the KCB sequences to NKCB, and vice versa. Further analyses of KCB will help us to understand the origin and evolutionary history of KCB.

Characteristics of HIV-Tat Protein Transduction Domain: Jong-Sub Yoon , Yong-Tae Jung , Seong-Karp Hong , Sun-Hwa Kim , Min-Chul Shin , Dong-Gun Lee , Wan-Shik Shin , Woo-Sung Min , Soon-Young Paik; J. Microbiol. 2004;42(4):328-335.; DOI: https://doi.org/2103 [pii]

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Abstract: The human immunodeficiency virus type 1 (HIV-1) Tat protein transduction domain (PTD), which contains rich arginine and lysine residues, is responsible for the highly efficient transduction of protein through the plasma membrane. In addition, it can be secreted from infected cells and has the ability to enter neighboring cells. When the PTD of Tat is fused to proteins and exogenously added to cells, the fusion protein can cross plasma membranes. Recent reports indicate that the endogenously expressed Tat fusion protein can demonstrate biodistribution of several proteins. However, intercellular transport and protein transduction have not been observed in some studies. Therefore, this study examined the intercellular transport and protein transduction of the Tat protein. The results showed no evidence of intercellular transport (biodistribution) in a cell culture. Instead, the Tat fusion peptides were found to have a significant effect on the transduction and intercellular localization properties. This suggests that the HIV-1 PTD passes through the plasma membrane in one direction.

Characterization and Signature Pattern Analysis of Korean Clade HIV-1 Using nef Gene Sequences: Chan Seung Park , Dong Hun Lee , Keon Myung Lee , Chan-Hee Lee; J. Microbiol. 2008;46(1):88-94.; DOI: https://doi.org/10.1007/s12275-007-0156-x

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3 Citations

Abstract: Phylogenetic studies of the HIV-1 gene sequences isolated from Korean patients have suggested that most of Korean isolates belong to the subtype B strain. This study aims to characterize the Korean clade by molecular phylogenetic analysis using all of the Korean nef gene sequences registered in the NCBI GenBank (N=422), in addition to 41 reference strains and 94 foreign isolates. Through phylogenetic analyses, we verified that most of the Korean isolates belonged to the subtype B, where 78.8% are clustered exclusively of foreign isolates. This cluster has been named the Korean clade subtype B (KCB) in order to distinguish it from other subtype B clusters. Genetic distance analysis suggested that the KCB cluster was more homogeneous and clearly distinctive from the non-Korean clade subtype B (NKCB). Comparison of consensus amino acid sequences from KCB and NKCB revealed that characteristic KCB signature amino acid patterns composed of 11 amino acid residues, whose frequencies in the KCB were significantly higher than in the NKCB. The KCB signature amino acid residues were critical in identifying KCB from NKCB, since substitution of the NKCB sequences with KCB signature amino acids relocated them to the Koran clade, and vice versa.

Studies on the Inhibition of HIV Replication with a Number of RRE Decoy Derivatives: Lee , Seong Wook; J. Microbiol. 1998;36(4):308-315.

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Abstract: RRE decoys are short RNA oligonucleotides corresponding to the HIV Rev response element (RRE) sequence, which protect cells from HIV replication by inhibiting the binding of the HIV regulatory protein Rev to the authentic HIV RRE region. Previously minimal RRE decoy containing the 13-nucleotide primary Rev binding domain of RRE was described to be a potent inhibitor of HIV in CEM cells. In this report, we analyzed and compared the ability of a series of RRE decoy derivatioves to inhibit HIV replication in CEM cells to develop increasingly effective RRE decoy. Using an improved tRNA cassette to express high level of RRE transcripts in cells, we found that a variant form of stem-loop II(SLII) binding domain of wild type RRE termed RRE40 was more potent than any other RRE decoys previously developed or tested here and protected all cells most effectively from HIV. RRE40 was previously selected in vitro which binds to Rev protein 10-fold better than wild type RRE. CEM cells expressing RRE40 decoy RNAE40 decoys inhibit HIV specifically by sequestering Rev binding to the authentic RRE target in HIV RNA and indicated that RRE40 RNA identified by using in vitro binding studies also binds Rev in cells. These obserbations have important implications for experiments involving optimization of clinical application of RNA decoy based gene therapy protocol against HIV.

Production and Characterization of Monoclonal Antibodies to Human Immunodeficiency Virus Type 1 gp120 Envelope Glycoprotein: Choi, Eui Yul , Ryu, Ji Yoon , Lee, Yoon , Ha, Sung Gil , Chung, So Young , Park, Sang Yeol , Nham, Sang Uk , Lee, Young Ik , Park, Jin Seu; J. Microbiol. 1998;36(1):59-65.

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Abstract: Monoclonal antibodies to human immunodeficiency virus type 1 envelope glycoprotein gp 120(HIV-1 gp120) were produced and characterized. For immunogen recombinant gp120 polypeptide expressed in bacteria was prepared and injected into mice. From two fusion experiments, twenty hybridomas secreting monoclonal antibodies against the recombinant gp120 were initially screened by immunodot blot analysis. Among the antibodies, 15 of them showed strong reactivities with the recombinant protein expressed in bacteria in Western blot and thus it was tested if these could react with the recombinant protein expressed in insect cells. All of the 15 antibodies immunostained the protein band with varing degrees of reactivities. Next, we tested whether the antibodies recognize authentic gp120 protein expressed in mammalian cells. COS-1 cells were tranfected with the cDNA encoding gp120 protein, and the transiently ecpressed protein were analyzed with the mAbs by Western blot analysis and immunofluorescence microscopy. Six of the monoclonal antibodies reacted with the protein band of authentic gp120 expressed in mammalian cells in the Western blot, and five stained the cell periphery of the transfected COS-1 cells in immunofluorescence. The mAbs described in this study should prove to be useful tools for the biochemical, immunological and structural analysis of HIV-1 gp120 envelope glycoprotein.

Phylogenetic Analysis of the HIV-1 nef Gene from Korean Isolates: Dong-Hun Lee , Yeup Yoon , Chan-Hee Lee; J. Microbiol. 2003;41(3):232-238.

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Abstract: Previous phylogenetic studies on human immunodeficiency virus type 1 (HIV-1) isolated from Korean patients suggest that the major subtype of Korean isolate is subtype B. In this subtype, some of the Korean isolates seem to be clustered exclusively of foreign isolates. Presence of this so-called “Korean clade” among Korean isolates is unique but needs verification since the number of Korean isolates used in previous studies was limited. This study aimed to identify the presence of the “Korean clade” by molecular phylogenetic analysis using all the Korean nef gene sequences registered in the NCBI GenBank (N=243) together with 32 reference strains and 77 foreign isolates. Extensive analysis of the nef gene nucleotide sequences by neighbor-joining method revealed the following. Most (83.1%) of the Korean isolates belonged to subtype B, and 81.2% of subtype B were clustered together and excluded foreign isolates (bootstrap value=91.9%). Within Korean subtype B cluster, no characteristic subcluster formation was evident since the bootstrap values for the subcluster were very low. Due to limited information, the phylogenetic analysis failed to identify the epidemiological linkage among specific groups such as homosexuals and hemophiliacs within the Korean subtype B cluster. Detailed analysis and epidemiological information are needed to clarify the origin and significance of the Korean subtype B cluster.

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