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https://www.readbyqxmd.com/read/29156603/adding-an-artificial-tail-anchor-to-a-peptide-based-hiv-1-fusion-inhibitor-for-improvement-of-its-potency-and-resistance-profile
#1
Shan Su, Zhenxuan Ma, Chen Hua, Weihua Li, Lu Lu, Shibo Jiang
Peptides derived from the C-terminal heptad repeat (CHR) of human immunodeficiency virus type 1 (HIV-1) envelope protein transmembrane subunit gp41, such as T20 (enfuvirtide), can bind to the N-terminal heptad repeat (NHR) of gp41 and block six-helix bundle (6-HB) formation, thus inhibiting HIV-1 fusion with the target cell. However, clinical application of T20 is limited because of its low potency and genetic barrier to resistance. HP23, the shortest CHR peptide, exhibits better anti-HIV-1 activity than T20, but the HIV-1 strains with E49K mutations in gp41 will become resistant to it...
November 20, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29156381/structure-based-methods-to-predict-mutational-resistance-to-diarylpyrimidine-non-nucleoside-reverse-transcriptase-inhibitors
#2
Syeda Maryam Azeem, Alecia N Muwonge, Nehaben Thakkar, Kristina W Lam, Kathleen M Frey
Resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) is a leading cause of HIV treatment failure. Often included in antiviral therapy, NNRTIs are chemically diverse compounds that bind an allosteric pocket of enzyme target reverse transcriptase (RT). Several new NNRTIs incorporate flexibility in order to compensate for lost interactions with amino acid conferring mutations in RT. Unfortunately, even successful inhibitors such as diarylpyrimidine (DAPY) inhibitor rilpivirine are affected by mutations in RT that confer resistance...
November 9, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/29152052/discovery-of-thiophene-3-2-d-pyrimidine-derivatives-as-potent-hiv-1-nnrtis-targeting-the-tolerant-region-i-of-nnibp
#3
Dongwei Kang, Xiao Ding, Gaochan Wu, Zhipeng Huo, Zhongxia Zhou, Tong Zhao, Da Feng, Zhao Wang, Ye Tian, Dirk Daelemans, Erik De Clercq, Christophe Pannecouque, Peng Zhan, Xinyong Liu
Our previous studies led us to conclude that thiophene[3,2-d]pyrimidine is a promising scaffold for diarylpyrimidine (DAPY)-type anti-HIV agents with potent activity against resistance-associated human immunodeficiency virus (HIV) variants (J. Med. Chem. 2016, 59, 7991-8007; J. Med. Chem. 2017, 60, 4424-4443). In the present study, we designed and synthesized a series of thiophenepyrimidine derivatives with various substituents in the right wing region of the structure with the aim of developing new interactions with the tolerant region I of the binding pocket of the HIV-1 non-nucleoside reverse transcriptase (NNRTI), and we evaluated their activity against a panel of mutant HIV-1 strains...
November 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29136775/high-parathyroid-hormone-concentration-in-tenofovir-treated-patients-are-due-to-inhibition-of-calcium-sensing-receptor-activity
#4
Alessandra Mingione, Katia Maruca, Federica Chiappori, Francesca Pivari, Caterina Brasacchio, Tiziana Quirino, Ivan Merelli, Laura Soldati, Paolo Bonfanti, Stefano Mora
Bone health impairment is a common finding in HIV-infected patients on antiretroviral treatment. High serum parathyroid hormone (PTH) concentration in patients on antiretroviral treatment containing tenofovir disoproxil fumarate (TDF) has been reported. Hyperparathyroidism was not always sustained by a reduction in vitamin D concentration. We thus hypothesized a direct inhibitory effect of TDF on the Calcium-sensing receptor (CaSR), leading to hyperparathyroidism. Human embryonic kidney cells were transfected with CASR wild-type gene or mutated in different sites (N124K, T1051G, C788T, T888M)...
November 7, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29128752/the-roles-of-five-conserved-lentiviral-rna-structures-in-hiv-1-replication
#5
Yang Liu, Jianbo Chen, Olga A Nikolaitchik, Belete A Desimmie, Steven Busan, Vinay K Pathak, Kevin M Weeks, Wei-Shau Hu
The HIV-1 RNA genome contains complex structures with many structural elements playing regulatory roles during viral replication. A recent study has identified multiple RNA structures with unknown functions that are conserved among HIV-1 and two simian immunodeficiency viruses. To explore the roles of these conserved RNA structures, we introduced synonymous mutations into the HIV-1 genome to disrupt each structure. These mutants exhibited similar particle production, viral infectivity, and replication kinetics relative to the parent NL4-3 virus...
November 9, 2017: Virology
https://www.readbyqxmd.com/read/29113016/cryptococcal-dissemination-to-the-central-nervous-system-requires-the-vacuolar-calcium-transporter-pmc1
#6
Eamim D Squizani, Natália K Oliveira, Júlia C V Reuwsaat, Bárbara M Marques, William Lopes, Alexandra L Gerber, Ana Tereza R de Vasconcelos, Sophie Lev, Julianne T Djordjevic, Augusto Schrank, Marilene H Vainstein, Charley C Staats, Lívia Kmetzsch
Cryptococcus neoformans is a basidiomycetous yeast and the cause of cryptococcosis in immunocompromised individuals. The most severe form of the disease is meningoencephalitis, which is one of the leading cause of death in HIV/AIDS patients. In order to access the central nervous system (CNS), C. neoformans relies on the activity of certain virulence factors such as urease, which allows transmigration through the blood-brain barrier (BBB). In the present study, we demonstrate that the calcium transporter Pmc1 enables C...
November 7, 2017: Cellular Microbiology
https://www.readbyqxmd.com/read/29110871/prevalence-of-rifampicin-resistant-mycobacterium-tuberculosis-among-human-immunodeficiency-virus-seropositive-patients-and-their-treatment-outcomes
#7
C K Vidyaraj, A Chitra, S Smita, M Muthuraj, S Govindarajan, B Usharani, S Anbazhagi
Multidrug resistant (MDR) and extensively drug resistant tuberculosis (TB) are a threat to the TB control programs in developing countries, and the situation is worsened by the human immunodeficiency virus (HIV) pandemic. This study was performed to correlate treatment outcome with the resistance patterns in HIV-seropositive patients coinfected with pulmonary TB. Sputum specimens were collected from 1643 HIV-seropositive patients and subjected to microscopy and liquid culture for TB. The smear- and culture-positive Mycobacterium tuberculosis isolates were subjected to Genotype MTBDRplus assay version 2...
December 2017: Journal of Epidemiology and Global Health
https://www.readbyqxmd.com/read/29093081/analysis-of-select-hsv-1-proteins-for-restriction-of-human-immunodeficiency-virus-type-1-the-hsv-1-gm-protein-potently-restricts-hiv-1-by-preventing-the-intracellular-transport-and-processing-of-env-gp160
#8
Sachith Polpitiya Arachchige, Wyatt Henke, Ankita Pramanik, Maria Kalamvoki, Edward B Stephens
Proteins encoded by viruses that impair or shutdown specific host cell functions during replication can be used as probes to identify potential proteins/pathways used in the replication of viruses from other families. We screened nine proteins from herpes simplex virus type 1 (HSV-1) for the ability to enhance or restrict human immunodeficiency virus type 1 (HIV-1) replication. We show that several HSV-1 proteins (glycoprotein M (gM), US3 and UL24) potently restricted the replication of HIV-1. Unlike UL24 and US3, which reduced viral protein synthesis, we observed that gM restriction of HIV-1 occurred through interference of the processing and transport of gp160, resulting in a significantly reduced level of mature gp120/gp41 released from cells...
November 1, 2017: Journal of Virology
https://www.readbyqxmd.com/read/29070877/probing-resistance-mutations-in-retroviral-integrases-by-direct-measurement-of-dolutegravir-fluorescence
#9
Eloïse Thierry, Samuel Lebourgeois, Françoise Simon, Olivier Delelis, Eric Deprez
FDA-approved integrase strand transfer inhibitors (raltegravir, elvitegravir and dolutegravir) efficiently inhibit HIV-1 replication. Here, we present fluorescence properties of these inhibitors. Dolutegravir displays an excitation mode particularly dependent on Mg(2+) chelation, allowing to directly probe its Mg(2+)-dependent binding to the prototype foamy virus (PFV) integrase. Dolutegravir-binding studied by both its fluorescence anisotropy and subsequent emission enhancement, strictly requires a preformed integrase/DNA complex, the ten terminal base pairs from the 3'-end of the DNA reactive strand being crucial to optimize dolutegravir-binding in the context of the ternary complex...
October 25, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29069622/intramuscular-delivery-of-replication-defective-herpes-simplex-virus-gives-antigen-expression-in-muscle-syncytia-and-improved-protection-against-pathogenic-hsv-2-strains
#10
Fernando Diaz, Sean Gregory, Hiroshi Nakashima, Mariano S Viapiano, David M Knipe
Herpes simplex virus 2 (HSV-2) is the leading cause of genital herpes and increases the risk of HIV infection, but there is no effective vaccine. A replication-defective HSV-2 mutant virus, dl5-29, is effective in animal models and has been in a phase I trial. Previous studies have shown that dl5-29 gives higher antibody responses and better protection when inoculated intramuscularly (IM) as compared with subcutaneously (SC). However, the basis for this effect has not been defined. We confirmed that IM inoculation of dl5-29 is more immunogenic and provides better protection than SC inoculation...
October 22, 2017: Virology
https://www.readbyqxmd.com/read/29054871/engineering-the-enantioselectivity-and-thermostability-of-a-%C3%AE-lactamase-from-microbacterium-hydrocarbonoxydans-for-the-kinetic-resolution-of-vince-lactam
#11
Shuaihua Gao, Shaozhou Zhu, Rong Huang, Hongxia Li, Hao Wang, Guojun Zheng
To produce promising biocatalysts, natural enzymes often need to be engineered to increase their catalytic performance. In this study, the enantioselectivity and thermostability of a (+)-γ-lactamase from Microbacterium hydrocarbonoxydans as the catalyst in the kinetic resolution of Vince lactam were improved. Enantiomerically pure (-)-Vince lactam is the key synthon in the synthesis of antiviral drugs such as carbovir and abacavir, which are used to fight against human HIV and hepatitis B viruses. The work was initialized by using the combinatorial active-site saturation test strategy to engineer the enantioselectivity of the enzyme...
October 20, 2017: Applied and Environmental Microbiology
https://www.readbyqxmd.com/read/29051495/the-%C3%AE-20-%C3%AE-21-of-gp120-is-a-regulatory-switch-for-hiv-1-env-conformational-transitions
#12
Alon Herschhorn, Christopher Gu, Francesca Moraca, Xiaochu Ma, Mark Farrell, Amos B Smith, Marie Pancera, Peter D Kwong, Arne Schön, Ernesto Freire, Cameron Abrams, Scott C Blanchard, Walther Mothes, Joseph G Sodroski
The entry of HIV-1 into target cells is mediated by the viral envelope glycoproteins (Env). Binding to the CD4 receptor triggers a cascade of conformational changes in distant domains that move Env from a functionally "closed" State 1 to more "open" conformations, but the molecular mechanisms underlying allosteric regulation of these transitions are still elusive. Here, we develop chemical probes that block CD4-induced conformational changes in Env and use them to identify a potential control switch for Env structural rearrangements...
October 19, 2017: Nature Communications
https://www.readbyqxmd.com/read/29049402/upward-trends-of-acquired-drug-resistances-in-ethiopian-hiv-1c-isolates-a-decade-longitudinal-study
#13
Andargachew Mulu, Melanie Maier, Uwe Gerd Liebert
BACKGROUND: The emergence, accumulation and spread of HIV-1 drug resistance strains in Africa could compromise the effectiveness of HIV treatment programs. This study was aimed at determining the incidence of virological failure and acquired drug resistance mutations overtime and identifying the most common mutational pathways of resistance in a well characterized HIV-1C infected Ethiopian cohort. METHODS: A total of 320 patients (220 ART naïve and 100 on first lines ART) were included and followed...
2017: PloS One
https://www.readbyqxmd.com/read/29040633/prevalence-of-pre-antiretroviral-treatment-drug-resistance-by-gender-age-and-other-factors-in-hiv-infected-individuals-initiating-therapy-in-kenya-2013-2014
#14
Rachel A Silverman, Ingrid A Beck, Catherine Kiptinness, Molly Levine, Ross Milne, Christine J McGrath, Steve Bii, Barbra A Richardson, Grace John-Stewart, Bhavna Chohan, Samah R Sakr, James N Kiarie, Lisa M Frenkel, Michael H Chung
Background: Pre-antiretroviral-treatment drug resistance (PDR) is a predictor of HIV treatment failure. We determined PDR-prevalence and correlates in a Kenyan cohort. Methods: We conducted a cross-sectional analysis of antiretroviral (ARV) treatment-eligible HIV-infected participants in 2013-2014 at three clinics. PDR was defined as ≥2% mutant-frequency in a participant's HIV-quasispecies at pol codons K103N, Y181C, G190A, M184 V, or K65R by oligonucleotide ligation assay...
October 10, 2017: Journal of Infectious Diseases
https://www.readbyqxmd.com/read/29040325/trim5%C3%AE-spry-coiled-coil-interactions-optimize-avid-retroviral-capsid-recognition
#15
Marcin D Roganowicz, Sevnur Komurlu, Santanu Mukherjee, Jacek Plewka, Steven L Alam, Katarzyna A Skorupka, Yueping Wan, Damian Dawidowski, David S Cafiso, Barbie K Ganser-Pornillos, Edward M Campbell, Owen Pornillos
Restriction factors are important components of intrinsic cellular defense mechanisms against viral pathogens. TRIM5α is a restriction factor that intercepts the incoming capsid cores of retroviruses such as HIV and provides an effective species-specific barrier to retroviral infection. The TRIM5α SPRY domain directly binds the capsid with only very weak, millimolar-level affinity, and productive capsid recognition therefore requires both TRIM5α dimerization and assembly of the dimers into a multivalent hexagonal lattice to promote avid binding...
October 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/29039614/substitutions-of-rtl228-and-or-l229-are-involved-in-the-regulation-of-replication-and-hbsag-secretion-in-hepatitis-b-virus-and-do-not-affect-susceptibility-to-nucleos-t-ide-analogs
#16
Bo Qin, Yechao Zhou, Guozhong Zhou, Xiuping Xu, Yanan Wang, Jinkun Chen
Nucleos(t)ide analogs (NAs) are widely used in the treatment of hepatitis B virus (HBV) and human immunodeficiency virus (HIV). The mutation L210W of HIV‑1 reverse transcriptase (RT) is one of the six principal mutations which confer in vivo resistance to zidovudine. Due to the similar 3D‑structure and high conservation between HIV‑RT and HBV‑RT, the present study aimed to clarify whether corresponding mutations in HBV may decrease its susceptibility to relevant NAs. Mutations including rtL228C/W, rtL229W and rtL228W/L229W were introduced into a HBV replication competent plasmid by fusion polymerase chain reaction...
December 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29029095/identification-of-novel-bifunctional-hiv-1-reverse-transcriptase-inhibitors
#17
Ming-Tain Lai, Paul Tawa, Anick Auger, Deping Wang, Hua-Poo Su, Youwei Yan, Daria J Hazuda, Michael D Miller, Ernest Asante-Appiah, Roman A Melnyk
Objectives: The increasing prevalence of mutations in HIV-1 reverse transcriptase (RT) that confer resistance to existing NRTIs and NNRTIs underscores the need to develop RT inhibitors with novel mode-of-inhibition and distinct resistance profiles. Methods: Biochemical assays were employed to identify inhibitors of RT activity and characterize their mode of inhibition. The antiviral activity of the inhibitors was assessed by cell-based assays using laboratory HIV-1 isolates and MT4 cells...
September 26, 2017: Journal of Antimicrobial Chemotherapy
https://www.readbyqxmd.com/read/29028476/differential-interaction-between-human-and-murine-crm1-and-lentiviral-rev-proteins
#18
Yan Yue, Ayse K Coskun, Navneet Jawanda, Jim Auer, Richard E Sutton
Mice have multiple obstacles to HIV replication, including a block of unspliced and partially spliced viral mRNA nuclear export. In human, Rev binds to the Rev-response element and human (h) Crm1, facilitating nuclear export of RRE-containing viral RNAs. Murine (m) Crm1 is less functional than hCrm1 in this regard. Here we demonstrated that in biochemical experiments mCrm1 failed to interact with HIV Rev whereas hCrm1 did. In genetic experiments in human cells, we observed a modest but significant differential effect between mCrm1 and hCrm1, which was also true of other lentiviral Revs tested...
October 10, 2017: Virology
https://www.readbyqxmd.com/read/29019352/hot-news-gene-therapy-with-crispr-cas9-coming-to-age-for-hiv-cure
#19
Vicente Soriano
The huge success of current antiretroviral therapy is mediated by a triple effect: (i) Halting progression to AIDS in infected persons; (ii) reducing the risk of transmission to contacts (treatment as prevention); and (iii) minimizing the risk of HIV acquisition treating uninfected persons at risk (pre-exposure prophylaxis). However, UNAIDS has estimated that only 70% of infected people globally are diagnosed, only 53% are treated, and overall 44% have undetectable viral load, which is the necessary request for ensuring any antiretroviral benefit...
October 2017: AIDS Reviews
https://www.readbyqxmd.com/read/28980928/optimizing-expression-of-antiviral-cyanovirin-n-homology-gene-using-response-surface-methodology-and-protein-structure-prediction
#20
H Lotfi, M A Hejazi, M K Heshmati, S A Mohammadi, N Zarghami
Cyanovirin-N (CVN) is well known as an anti-HIV protein. The efficient production of low cost microbicides for preventing the HIV-infection  has lately become a requirement worldwide. The aim of the present study was to optimize the expression of antiviral Cyanovirin-N homology gene found in the indigenous strain of Nostoc ellipsospourum LZN using Response Surface Methodology (RSM) and Protein Structure Analysis. Optimization of three induction factors (IPTG concentration (0.1, 0.55 and 1mM), temperature for bacterial growth (20, 28...
September 30, 2017: Cellular and Molecular Biology
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