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https://www.readbyqxmd.com/read/28426273/preclinical-development-of-bcg-hiva-2auxo-int-harboring-an-integrative-expression-vector-for-a-hiv-tb-pediatric-vaccine-enhancement-of-stability-and-specific-hiv-1-t-cell-immunity
#1
Aakash Mahant, Narcís Saubi, Yoshiki Eto, Núria Guitart, Josep M ª Gatell, Tomáš Hanke, Joan Joseph
One of the critical issues that should be addressed in the development of a BCG-based HIV vaccine is genetic plasmid stability. Therefore, to address this issue we have considered using integrative vectors and the auxotrophic mutant of BCG complemented with a plasmid carrying a wild-type complementing gene. In this study, we have constructed an integrative E. coli-mycobacterial shuttle plasmid, p2auxo.HIVA(int), expressing the HIV-1 clade A immunogen HIVA. This shuttle vector employs an antibiotic resistance-free mechanism for plasmid selection and maintenance...
April 20, 2017: Human Vaccines & Immunotherapeutics
https://www.readbyqxmd.com/read/28424288/virion-associated-vpr-alleviates-a-post-integration-block-to-hiv-1-infection-of-dendritic-cells
#2
Caitlin M Miller, Hisashi Akiyama, Luis M Agosto, Ann Emery, Chelsea R Ettinger, Ronald I Swamstrom, Andrew J Henderson, Suryaram Gummuluru
Viral protein R (Vpr) is an HIV-1 accessory protein whose function remains poorly understood. In this report, we sought to determine the requirement of Vpr in facilitating HIV-1 infection of monocyte-derived dendritic cells (MDDCs), one of the first cells to encounter virus in the peripheral mucosal tissues. We characterize in this report a significant restriction to Vpr-deficient virus replication and spread in MDDCs alone and in cell-to-cell spread in MDDC - CD4(+) T cell co-cultures. This restriction to HIV-1 replication in MDDCs was observed in a single round of virus replication and was rescued by expression of Vpr in trans in the incoming virion...
April 19, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28424281/distinct-roles-of-vaccinia-virus-nf-kb-inhibitor-proteins-a52-b15-and-k7-in-the-immune-response
#3
Mauro Di Pilato, Ernesto Mejías-Pérez, Carlos Oscar S Sorzano, Mariano Esteban
Poxviruses use a complex strategy to escape immune control, by expressing immunomodulatory proteins that could limit their use as vaccine vectors. To test the role of poxvirus NF-κB pathway inhibitors A52, B15 and K7 in immunity, we deleted their genes in a NYVAC vaccinia virus strain that expresses HIV-1 clade C antigens. After infection of mice, ablation of A52R, B15R and K7R increased dendritic cell, natural killer cell and neutrophil migration as well as chemokine/cytokine expression. Revertant viruses for these genes confirmed their role in inhibiting the innate immune system...
April 19, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28392143/development-of-a-dna-vaccine-expressing-a-secreted-hiv-1-gp41-ectodomain-that-includes-the-membrane-proximal-external-region
#4
Luca Melnychuk, Lara Ajamian, Patrick Jean-Pierre, Jiaming Liang, Romina Gheorghe, Mark A Wainberg, Gerasimos J Zaharatos
A limited number of sites on the HIV-1 Envelope protein are vulnerable to broadly neutralizing antibodies (bnAbs). One of these sites, the membrane proximal external region (MPER), is located at the C-terminus of the gp41 ectodomain (gp41ecto). This highly conserved sequence is bound by several well-characterized bnAbs. Efforts to produce a gp41 immunogen are in part hampered by the MPER's hydrophobicity and propensity to induce aggregation. We sought to produce a DNA vaccine expressing a gp41ecto that is both secreted from mammalian cells and maintains binding by bnAbs to the MPER...
April 6, 2017: Vaccine
https://www.readbyqxmd.com/read/28390939/guanine-%C3%AE-carboxy-nucleoside-phosphonate-g-%C3%AE-cnp-shows-a-different-inhibitory-kinetic-profile-against-the-dna-polymerases-of-human-immunodeficiency-virus-hiv-and-herpes-viruses
#5
Jan Balzarini, Michael Menni, Kalyan Das, Lizette van Berckelaer, Alan Ford, Nuala M Maguire, Sandra Liekens, Paul E Boehmer, Eddy Arnold, Matthias Götte, Anita R Maguire
α-Carboxy nucleoside phosphonates (α-CNPs) are modified nucleotides that represent a novel class of nucleotide-competing reverse transcriptase (RT) inhibitors (NcRTIs). They were designed to act directly against HIV-1 RT without the need for prior activation (phosphorylation). In this respect, they differ from the nucleoside or nucleotide RTIs [N(t)RTIs] that require conversion to their triphosphate forms before being inhibitory to HIV-1 RT. The guanine derivative (G-α-CNP) has now been synthesized and investigated for the first time...
April 5, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28388673/proteolysis-of-mature-hiv-1-p6-gag-protein-by-the-insulin-degrading-enzyme-ide-regulates-virus-replication-in-an-env-dependent-manner
#6
Friedrich Hahn, Adrian Schmalen, Christian Setz, Melanie Friedrich, Stefan Schlößer, Julia Kölle, Robert Spranger, Pia Rauch, Kirsten Fraedrich, Tatjana Reif, Julia Karius-Fischer, Ashok Balasubramanyam, Petra Henklein, Torgils Fossen, Ulrich Schubert
There is a significantly higher risk for type II diabetes in HIV-1 carriers, albeit the molecular mechanism for this HIV-related pathology remains enigmatic. The 52 amino acid HIV-1 p6 Gag protein is synthesized as the C-terminal part of the Gag polyprotein Pr55. In this context, p6 promotes virus release by its two late (L-) domains, and facilitates the incorporation of the viral accessory protein Vpr. However, the function of p6 in its mature form, after proteolytic release from Gag, has not been investigated yet...
2017: PloS One
https://www.readbyqxmd.com/read/28381554/dna-mutagenic-activity-and-capacity-for-hiv-1-restriction-of-the-cytidine-deaminase-apobec3g-depends-on-whether-dna-or-rna-binds-to-tyrosine-315
#7
Bogdan Polevoda, Rebecca Joseph, Alan E Friedman, Ryan P Bennett, Rebecca Greiner, Thareendra De Zoysa, Ryan A Stewart, Harold C Smith
APOBEC3G (A3G) belongs to the AID/APOBEC protein family of cytidine deaminases (CDA) that bind to nucleic acids. A3G mutates the HIV genome by deamination of dC to dU, leading to accumulation of virus-inactivating mutations. Binding to cellular RNAs inhibits A3G binding to substrate single-stranded (ss) DNA and CDA activity. RNA and ssDNA bind to the same three A3G tryptic peptides (amino acids 181-194, 314-320, and 345-374) that form parts of a continuously exposed protein surface extending from the catalytic domain in the C-terminus of A3G to its N-terminus...
April 5, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28379444/a-dead-box-protein-acts-through-rna-to-promote-hiv-1-rev-rre-assembly
#8
Rajan Lamichhane, John A Hammond, Raymond F Pauszek, Rae M Anderson, Ingemar Pedron, Edwin van der Schans, James R Williamson, David P Millar
The HIV-1 Rev protein activates nuclear export of unspliced and partially spliced viral RNA transcripts, which encode the viral genome and the genes encoding viral structural proteins, by binding to and oligomerizing on the Rev Response Element (RRE). The human DEAD-box protein 1 (DDX1) enhances the RNA export activity of Rev through an unknown mechanism. Using a single-molecule assembly assay and various DDX1 mutants, we show that DDX1 acts through the RRE RNA to specifically accelerate the nucleation step of the Rev-RRE assembly process...
March 31, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28377526/the-r263k-dolutegravir-resistance-associated-substitution-progressively-decreases-hiv-1-integration
#9
Thibault Mesplède, Jing Leng, Hanh Thi Pham, Jiaming Liang, Yudong Quan, Yingshan Han, Mark A Wainberg
Human immunodeficiency virus (HIV) infection persists despite decades of active antiretroviral therapy (ART), effectively preventing viral eradication. Treatment decreases plasma viral RNA, but viral DNA persists, mostly integrated within the genome of nucleated blood cells. Viral DNA blood levels correlate with comorbidities and the rapidity of viral rebound following treatment interruption. To date, no intervention aiming at decreasing HIV DNA levels below those attained through ART has been successful. This includes use of some integrase inhibitors either as part of ART or in treatment intensification studies...
April 4, 2017: MBio
https://www.readbyqxmd.com/read/28371730/systematic-profiling-of-substrate-binding-response-to-multidrug-resistant-mutations-in-hiv-1-protease-implication-for-combating-drug-resistance
#10
Yonglei Lv, Jianbing Li, Jianhua Fang, Xiufeng Jiao, Lumin Yan, Baifeng Shan
Human immunodeficiency virus 1 (HIV-1) protease (PR) represents one of the primary targets for developing antiviral agents for the treatment of HIV-infected patients. However, a number of multidrug-resistant mutations in the enzyme have been observed over the past decades, largely limiting the application of PR inhibitors in antiviral therapy. A systematic investigation of the intermolecular interaction between the multidrug-resistant mutants of HIV-1 PR and its substrates would help to establish a complete profile of substrate response to PR mutations and to design new antiviral agents combating drug resistance...
March 18, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28363735/evolution-of-tenofovir-resistant-hiv-1-isolates-exposed-to-tenofovir-alafenamide-dose-escalation
#11
Stephanie Cox, Nicolas Margot, Renee Ram, Audun Johnson, Michael Miller, Christian Callebaut
Resistance selection experiments using HIV-1 isolates harboring pre-existing tenofovir (TFV)-resistance (K65R, 3TAMs, and Q151M complex) were carried out with the novel tenofovir prodrug tenofovir alafenamide (TAF) as well as with tenofovir (TFV), to investigate the potential for additional resistance development in the presence of TAF or TFV. Extended resistance selection of these TFV resistance associated mutations (RAMs)-containing viruses with TAF or TFV did not lead to the accumulation of additional known RAMs, or significant additional phenotypic resistance, after 6 months in culture...
March 28, 2017: Antiviral Research
https://www.readbyqxmd.com/read/28360890/driving-hiv-1-into-a-vulnerable-corner-by-taking-advantage-of-viral-adaptation-and-evolution
#12
REVIEW
Shigeyoshi Harada, Kazuhisa Yoshimura
Anti-retroviral therapy (ART) is crucial for controlling human immunodeficiency virus type-1 (HIV-1) infection. Recently, progress in identifying and characterizing highly potent broadly neutralizing antibodies has provided valuable templates for HIV-1 therapy and vaccine design. Nevertheless, HIV-1, like many RNA viruses, exhibits genetically diverse populations known as quasispecies. Evolution of quasispecies can occur rapidly in response to selective pressures, such as that exerted by ART and the immune system...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28356533/a-lipopeptide-hiv-1-2-fusion-inhibitor-with-highly-potent-in-vitro-ex-vivo-and-in-vivo-antiviral-activity
#13
Huihui Chong, Jing Xue, Shengwen Xiong, Zhe Cong, Xiaohui Ding, Yuanmei Zhu, Zixuan Liu, Ting Chen, Yifan Feng, Lei He, Yan Guo, Qiang Wei, Yusen Zhou, Chuan Qin, Yuxian He
Peptides derived from the C-terminal heptad repeat (CHR) region of the HIV-1 fusogenic protein gp41 are potent viral entry inhibitors, and currently enfuvirtide (T-20) is the only one for clinical use; however, emerging drug-resistance largely limits its efficacy. In this study, we generated a novel lipopeptide inhibitor, named LP-19, by integrating multiple design strategies, including an N-terminal M-T hook structure, HIV-2 sequence, intra-helical salt-bridges, and a membrane-anchoring lipid tail. LP-19 showed stable binding affinity and highly potent, broad and long-lasting antiviral activity...
March 29, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28346521/hiv-1-gp120-envelope-glycoprotein-determinants-for-cytokine-burst-in-human-monocytes
#14
Benoît Levast, Lucie Barblu, Mathieu Coutu, Jérémie Prévost, Nathalie Brassard, Adam Peres, Camille Stegen, Joaquín Madrenas, Daniel E Kaufmann, Andrés Finzi
The first step of HIV infection involves the interaction of the gp120 envelope glycoprotein to its receptor CD4, mainly expressed on CD4+ T cells. Besides its role on HIV-1 entry, the gp120 has been shown to be involved in the production of IL-1, IL-6, CCL20 and other innate response cytokines by bystander, uninfected CD4+ T cells and monocytes. However, the gp120 determinants involved in these functions are not completely understood. Whether signalling leading to cytokine production is due to CD4 or other receptors is still unclear...
2017: PloS One
https://www.readbyqxmd.com/read/28342872/covalent-conjugation-of-the-equine-infectious-anemia-virus-gag-with-sumo
#15
Jinzhong Wang, Shuping Wen, Rui Zhao, Jing Qi, Zhao Liu, Weiwei Li, Jing An, Charles Wood, Ying Wang
The conjugation of small ubiquitin-like modifier (SUMO) to the target protein, namely, SUMOylation, is involved in the regulation of many important biological events including host-pathogen interaction. Some viruses have evolved to exploit the host SUMOylation machinery to modify their own protein. Retroviral Gag protein plays critical roles in the viral life cycle. The HIV-1 p6 and the Moloney murine leukemia virus CA have been reported to be conjugated with SUMO. In this study, we report for the first time, to our knowledge, the covalent conjugation of equine infectious anemia virus (EIAV) Gag with SUMO...
March 22, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28342375/nanozyme-based-bio-barcode-assay-for-high-sensitive-and-logic-controlled-specific-detection-of-multiple-dnas
#16
Xiaodong Lin, Yaqing Liu, Zhanhui Tao, Jinting Gao, Jiankang Deng, Jinjin Yin, Shuo Wang
Since HCV and HIV share a common transmission path, high sensitive detection of HIV and HCV gene is of significant importance to improve diagnosis accuracy and cure rate at early stage for HIV virus-infected patients. In our investigation, a novel nanozyme-based bio-barcode fluorescence amplified assay is successfully developed for simultaneous detection of HIV and HCV DNAs with excellent sensitivity in an enzyme-free and label-free condition. Here, bimetallic nanoparticles, PtAuNPs, present outstanding peroxidase-like activity and act as barcode to catalyze oxidation of nonfluorescent substrate of amplex red (AR) into fluorescent resorufin generating stable and sensitive "Turn On" fluorescent output signal, which is for the first time to be integrated with bio-barcode strategy for fluorescence detection DNA...
January 5, 2017: Biosensors & Bioelectronics
https://www.readbyqxmd.com/read/28338924/a-nonsynonymous-snp-catalog-of-mycobacterium-tuberculosis-virulence-genes-and-its-use-for-detecting-new-potentially-virulent-sublineages
#17
Natalya E Mikheecheva, Marina V Zaychikova, Alexander V Melerzanov, Valery N Danilenko
Mycobacterium tuberculosis is divided into several distinct lineages, and various genetic markers such as IS-elements, VNTR, and SNPs are used for lineage identification. We propose an M. tuberculosis classification approach based on functional polymorphisms in virulence genes. An M. tuberculosis virulence genes catalog has been established, including 319 genes from various protein groups, such as proteases, cell wall proteins, fatty acid and lipid metabolism proteins, sigma factors, toxin-antitoxin systems...
April 1, 2017: Genome Biology and Evolution
https://www.readbyqxmd.com/read/28336404/mapping-region-of-human-restriction-factor-apobec3h-critical-for-interaction-with-hiv-1-vif
#18
Masaaki Nakashima, Shinya Tsuzuki, Hiroaki Awazu, Akiko Hamano, Ayaka Okada, Hirotaka Ode, Masami Maejima, Atsuko Hachiya, Yoshiyuki Yokomaku, Nobuhisa Watanabe, Hirofumi Akari, Yasumasa Iwatani
The APOBEC3 (A3) family of cellular cytidine deaminases comprises seven members (A, B, C, D, F, G, and H) that potently inhibit retroviral replication. Human immunodeficiency virus type 1 (HIV-1) Vif is a small pleiotropic protein that specifically inactivates these enzymes, targeting them for ubiquitin-mediated proteasomal degradation. A3 Vif-interaction sites are presumed to fall into three distinct types: A3C/D/F, A3G, and A3H. To date, two types of A3G and A3C/D/F sites have been well characterized, whereas the A3H Vif-binding site remains poorly defined...
March 21, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28333133/fidelity-of-classwide-resistant-hiv-2-reverse-transcriptase-and-differential-contribution-of-k65r-to-the-accuracy-of-hiv-1-and-hiv-2-reverse-transcriptases
#19
Mar Álvarez, Alba Sebastián-Martín, Guillermo García-Marquina, Luis Menéndez-Arias
Nucleoside reverse transcriptase (RT) inhibitors constitute the backbone of current therapies against human immunodeficiency virus type 1 and type 2 (HIV-1 and HIV-2, respectively). However, mutational pathways leading to the development of nucleoside analogue resistance are different in both types of HIV. In HIV-2, resistance to all approved nucleoside analogues is conferred by the combination of RT substitutions K65R, Q151M and M184V. Nucleotide incorporation kinetic analyses of mutant and wild-type (WT) HIV-2 RTs show that the triple-mutant has decreased catalytic efficiency due to the presence of M184V...
March 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28321930/uncovering-allostery-and-regulation-in-samhd1-through-molecular-dynamics-simulations
#20
Kajwal Kumar Patra, Akash Bhattacharya, Swati Bhattacharya
The human sterile alpha motif and HD domain-containing protein 1 (SAMHD1) is a retroviral restriction factor in myeloid cells and non-cycling CD4+ T cells, a feature imputed to its phosphohydrolase activity-the enzyme depletes the cellular dNTP levels inhibiting reverse transcription. The functionally active form of SAMHD1 is an allosterically triggered tetramer which utilizes GTP-Mg(+2) -dNTP cross bridges to link and stabilize adjacent monomers. However, very little is known about how it assembles into a tetramer and how long the tetramer stays intact...
March 21, 2017: Proteins
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