Article
Biochemistry & Molecular Biology
Thomas W. Kirby, Scott A. Gabel, Eugene F. Derose, Lalith Perera, Juno M. Krahn, Lars C. Pedersen, Robert E. London
Summary: This study aims to identify small molecule ligands that can interfere with the formation of active HIV-1 reverse transcriptase (RT) by understanding its maturation process. The isolated polymerase domain p51 was utilized and ligands at subdomain interfaces were identified using computational analysis and experimental techniques, with their interactions further characterized. This study provides insight into the reverse transcription process of the virus and potential new drug targets.
Article
Biochemical Research Methods
Karina Pikalyova, Alexey Orlov, Arkadii Lin, Olga Tarasova, Marcou Gilles, Dragos Horvath, Vladimir Poroikov, Alexandre Varnek
Summary: A new methodology based on generative topographic mapping (GTM) was introduced for predicting the drug resistance of HIV strains. The approach combines high accuracy and interpretability, allowing for visualization and analysis of sequence space and treatment optimization. Several case studies demonstrate the practicality of this method.
Article
Chemistry, Medicinal
Giavana R. Prucha, Sean Henry, Klarissa Hollander, Zachary J. Carter, Krasimir A. Spasov, William L. Jorgensen, Karen S. Anderson
Summary: This study reports the synthesis of 34 compounds that covalently inhibit reverse transcriptase to overcome the issue of resistance to non-nucleoside reverse transcriptase inhibitors. Two of these inhibitors demonstrate biochemical, structural, enzyme kinetic, mass spectrometry, and antiviral activity against HIV-1.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Agriculture, Dairy & Animal Science
Jaco Bakker, Annemiek Maaskant, Merel Wegman, Dian G. M. Zijlmans, Patrice Hage, Jan A. M. Langermans, Edmond J. Remarque
Summary: We investigated the effect of various factors on the hematologic and serum biochemical values of captive rhesus and cynomolgus macaques. The results provide important reference intervals for evaluating experimental results and health control in these macaques. Our study highlights the need for standardized experimental groups and validated animal husbandry to improve the reproducibility of experiments.
Article
Chemistry, Medicinal
Xiangyi Jiang, Boshi Huang, Waleed A. Zalloum, Chin-Ho Chen, Xiangkai Ji, Zhen Gao, Jiaojiao Dai, Minghui Xie, Dongwei Kang, Erik De Clercq, Christophe Pannecouque, Xinyong Liu, Peng Zhan
Summary: Novel diarypyrimidine derivatives were designed based on previously reported HIV-1 NNRTIs BH-11c and XJ-10c to improve antiresistance and drug-like profiles. Compound 12g showed the highest inhibitory activity against wild-type and NNRTI-resistant HIV-1 strains, with EC50 values ranging from 0.024 to 0.0010 μM. Its improved antiresistance profile compared to ETR was explained by MD simulation study and it also showed improved water solubility and other drug-like properties. Compound 12g exhibited promising pharmacokinetics parameters and could be a potential lead compound for new antiretroviral drug development.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Cell Biology
Carl J. Balibar, Daniel J. Klein, Beata Zamlynny, Tracy L. Diamond, Zhiyu Fang, Carol A. Cheney, Jan Kristoff, Meiqing Lu, Marina Bukhtiyarova, Yangsi Ou, Min Xu, Lei Ba, Steven S. Carroll, Abdellatif El Marrouni, John F. Fay, Ashley Forster, Shih Lin Goh, Meigang Gu, Daniel Krosky, Daniel I. S. Rosenbloom, Payal Sheth, Deping Wang, Guoxin Wu, Matthias Zebisch, Tian Zhao, Paul Zuck, Jay Grobler, Daria J. Hazuda, Bonnie J. Howell, Antonella Converso
Summary: Antiretroviral therapy can inhibit HIV-1 replication but cannot cure the infection due to the persistence of a reservoir in the host genome. Reduction of this reservoir is important for HIV-1 cure. Some nonnucleoside reverse transcriptase inhibitors have shown selective cytotoxicity against HIV-1 in vitro, but their concentrations required are much higher than approved dosages. By focusing on this secondary activity, researchers have discovered bifunctional compounds called targeted activators of cell kill (TACK) that can kill HIV-1-infected cells at clinically achievable concentrations. These TACK molecules bind to the reverse transcriptase-p66 domain of monomeric Gag-Pol and act as allosteric modulators, promoting dimerization and premature intracellular viral protease activation, leading to death of HIV-1(+) cells. TACK molecules retain potent antiviral activity and selectively eliminate infected CD4(+) T cells, providing a potential immune-independent clearance strategy.
SCIENCE TRANSLATIONAL MEDICINE
(2023)
Article
Multidisciplinary Sciences
Cassandra Moats, Kimberly Cook, Kimberly Armantrout, Hugh Crank, Samantha Uttke, Kelly Maher, Rachele M. Bochart, George Lawrence, Michael K. Axthelm, Jeremy Smedley
Summary: This study found that perioperative prophylactic antibiotics have no role in reducing complication rates in SIV/SHIV-infected and uninfected macaques undergoing clean, minimally invasive surgeries. Furthermore, unnecessary antibiotic use in study animals should be eliminated to avoid confounding impacts on research models and the promotion of antimicrobial resistance.
Article
Virology
Maria E. Cilento, Xin Wen, Aaron B. Reeve, Obiaara B. Ukah, Alexa A. Snyder, Ciro M. Carrillo, Cole P. Smith, Kristin Edwards, Claudia C. Wahoski, Deborah R. Kitzler, Eiichi N. Kodama, Hiroaki Mitsuya, Michael A. Parniak, Philip R. Tedbury, Stefan G. Sarafianos
Summary: TDF and ISL are highly potent nucleoside reverse transcriptase inhibitors with different resistance profiles. This study found that ISL is sensitive to the K65R mutation, while TDF is sensitive to the M184V mutation. The sensitivity to these drugs also varies among different HIV subtypes, and the S68G polymorphism may enhance the fitness of drug-resistant mutants in certain genetic backgrounds.
Article
Immunology
Pinyi Lu, Dylan J. Guerin, Shu Lin, Sidhartha Chaudhury, Margaret E. Ackerman, Diane L. Bolton, Anders Wallqvist
Summary: A study evaluated the efficacy of a next generation liposome-based adjuvant in rhesus monkeys against HIV-1 infection, showing 90% protection. Analysis using machine learning and Cox proportional hazards regression revealed that ALFA enhanced Fc gamma receptor 2a-related binding antibody responses, reducing infection risk in male animals.
FRONTIERS IN IMMUNOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Javier Martinez del Rio, Nerea Lopez-Carrobles, Jesus I. Mendieta-Moreno, Oscar Herrera-Chacon, Adrian Sanchez-Ibanez, Jesus Mendieta, Luis Menendez-Arias
Summary: The combination of PCR and RTs has been widely used in RNA detection and gene expression analysis. Improving thermostability and nucleic acid binding affinity of RTs is crucial for enhancing the efficiency of these applications. This study investigated the effects of amino acid substitutions in the RT RNase H domain on its properties. It was found that specific substitutions resulted in loss of activity and mutations that improved cDNA synthesis efficiency also affected RNase H activity. This discovery provides evidence for a novel mechanism of RNase H inactivation.
JOURNAL OF MOLECULAR BIOLOGY
(2023)
Article
Microbiology
Wanat Sricharern, Supakarn Kaewchot, Phirabhat Saengsawang, Sarawan Kaewmongkol, Tawin Inpankaew
Summary: Bartonella quintana, a zoonotic pathogen with a global distribution, was found in long-tailed macaques in Thailand, indicating the potential role of these primates as reservoir hosts. Despite a low infection rate, the study suggests that long-tailed macaques may serve as a reservoir for B. quintana.
Article
Biotechnology & Applied Microbiology
Swati Jaiswal, Sarah K. Nyquist, Shayla Boyce, Tasneem Jivanjee, Samira Ibrahim, Joshua D. Bromley, G. James Gatter, Hannah Gideon, Kush Patel, Sharie Keanne Ganchua, Bonnie Berger, Sarah M. Fortune, JoAnne L. Flynn, Alex K. Shalek, Samuel M. Behar
Summary: This article describes the definition and characterization of the T cell receptor (TCR) repertoire in cynomolgus macaques, as well as the determination of its functional status through single cell RNA sequencing. The results show that cynomolgus macaques have a high genomic similarity with rhesus macaques and a significant sequence similarity with the human TCR repertoire. This is of great importance for analyzing T cell immune responses in cynomolgus macaques.
Article
Multidisciplinary Sciences
Chris Wymant, Daniela Bezemer, Francois Blanquart, Luca Ferretti, Astrid Gall, Matthew Hall, Tanya Golubchik, Margreet Bakker, Swee Hoe Ong, Lele Zhao, David Bonsall, Mariateresa de Cesare, George MacIntyre-Cockett, Lucie Abeler-Doerner, Jan Albert, Norbert Bannert, Jacques Fellay, M. Kate Grabowski, Barbara Gunsenheimer-Bartmeyer, Huldrych F. Gunthard, Pia Kivela, Roger D. Kouyos, Oliver Laeyendecker, Laurence Meyer, Kholoud Porter, Matti Ristola, Ard van Sighem, Ben Berkhout, Paul Kellam, Marion Cornelissen, Peter Reiss, Christophe Fraser
Summary: A highly virulent variant of subtype-B HIV-1 was discovered in the Netherlands. Infected individuals with this variant had significantly higher viral loads and faster decline in CD4 cells compared to other subtype-B strains. The increased virulence is attributed to the viral strain, and the variant emerged in the 1990s with increased transmissibility and an unfamiliar molecular mechanism of virulence.
Article
Virology
Shih-Han Hsieh, Fu-Hsien Yu, Kuo-Jung Huang, Chin-Tien Wang
Summary: RT modulates PR activation by affecting Gag-Pol/Gag-Pol interaction. Amino acid substitutions in RT destabilize RT and make it susceptible to PR degradation. LRM mutants exhibit reduced Gag cleavage efficiencies and attenuate the enhancing effect of EFV on Gag cleavage.
JOURNAL OF VIROLOGY
(2023)
Article
Biochemistry & Molecular Biology
Mahta Mansouri, Shawn Rumrill, Shane Dawson, Adam Johnson, Jo-Anne Pinson, Menachem J. Gunzburg, Catherine F. Latham, Nicholas Barlow, George W. Mbogo, Paula Ellenberg, Stephen J. Headey, Nicolas Sluis-Cremer, David Tyssen, Joseph D. Bauman, Francesc X. Ruiz, Eddy Arnold, David K. Chalmers, Gilda Tachedjian
Summary: Human immunodeficiency virus type I (HIV-1) is a major global health burden, and the emergence of drug-resistance mutations necessitates the development of novel drugs. In this study, a fragment-based drug discovery approach was used to optimize a hit fragment (compound B-1) that targets the viral protein reverse transcriptase (RT) in a novel site. Different compound series were synthesized and evaluated for their RT binding and inhibition, leading to the identification of a lead compound with promising inhibitory activity. This study offers a starting point for the development of novel dual inhibitors targeting the NNRTI-binding pocket and an adjacent site.