2019 Research Highlights

Alpha-carboxynucleoside phosphonates: direct-acting inhibitors of viral DNA polymerases

A new class of polymerase inhibitors mimic nucleotide triphosphates

Balzarini J, Ford A, Maguire NM, John J, Das K, Arnold E, Dehaen W, Maguire A. Future Med Chem. 2019 Jan;11(2):137-154.

PubMed PMID: 30648904

PubMedCentral PMCID: PMC6362432

The GTPase domain of MX2 interacts with the HIV-1 capsid, enabling its short isoform to moderate antiviral restriction

Restriction factor MX2 interacts with HIV-1 capsid through multiple contacts

Betancor G, Dicks MDJ, Jimenez-Guardeño JM, Ali NH, Apolonia L, Malim MH. Cell Rep. 2019 Nov 12;29(7):1923-1933.e3.

PubMed PMID: 31722207

PubMedCentral PMCID: PMC7391006

Epistasis and entrenchment of drug resistance in HIV-1 subtype B

HIVE researchers explore how viral populations mutate when treated with antiviral drugs.

Biswas A, Haldane A, Arnold E, Levy RM. Elife. 2019 Oct 8;8.

PubMed PMID: 31591964

PubMedCentral PMCID: PMC6783267

Intrinsic conformational dynamics of the HIV-1 genomic RNA 5’UTR

FRET experiments explore the complex higher-order structure of the HIV-1 genome.

Brigham BS, Kitzrow JP, Reyes JC, Musier-Forsyth K, Munro JB. Proc Natl Acad Sci U S A. 2019 116(21):10372-10381.

PubMed PMID: 31068467

PubMedCentral PMCID: PMC6534999

Epstein-Barr virus BORF2 inhibits cellular APOBEC3B to preserve viral genome integrity

Epstein-Barr virus, the causative agent of infectious mononucleosis and multiple cancers, utilizes a two-pronged approach to counteract restriction by APOBEC3B

Cheng AZ, Yockteng-Melgar J, Jarvis MC, Malik-Soni N, Borozan I, Carpenter MA, McCann JL, Ebrahimi D, Shaban NM, Marcon E, Greenblatt J, Brown WL, Frappier L, Harris RS. Nat Microbiol. 2019 Jan;4(1):78-88.

PubMed PMID: 30420783

PubMedCentral PMCID: PMC6294688

Novel Intersubunit Interaction Critical for HIV-1 Core Assembly Defines a Potentially Targetable Inhibitor Binding Pocket

Structure of HIV-1 RT/dsRNA initiation complex prior to nucleotide incorporation

HIVE Center members reveal the structure of a complex that mimics the reverse transcription initiation complex.

Das K, Martinez SE, DeStefano JJ, Arnold E. Proc Natl Acad Sci U S A 116, 7308-7313 (2019).

PubMed PMID: 30902895

PubMedCentral PMCID: PMC6462067

Comparison of affinity ranking using AutoDock-GPU and MM-GBSA scores for BACE-1 inhibitors in the D3R Grand Challenge 4

Estimates of surface area in affinity prediction are evaluated in a docking challenge.

El Khoury L, Santos-Martins D, Sasmal S, Eberhardt J, Bianco G, Ambrosio FA, Solis-Vasquez L, Koch A, Forli S, Mobley DL. J Comput Aided Mol Des. 2019 33(12):1011-1020.

PubMed PMID: 31691919

PubMedCentral PMCID: PMC7027993

Integrative modeling of the HIV-1 ribonucleoprotein complex

Coarse-grain models explore the complex of HIV-1 genomic RNA with integrase and nucleocapsid.

Goodsell DS, Jewett A, Olson AJ, Forli S. PLoS Comput Biol. 2019 Jun 13;15(6):e1007150.

PubMed PMID: 31194731

PubMedCentral PMCID: PMC6592547

Cryo-EM Structures of a Group II Intron Reverse Splicing into DNA

Cryoelectron microscopy captures the atomic details of group II introns in action.

Haack DB, Yan X, Zhang C, Hingey J, Lyumkis D, Baker TS, Toor N. Cell. 2019 178(3):612-623.

PubMed PMID: 31348888

PubMedCentral PMCID: PMC6662634

Influence of multiple-sequence-alignment depth on Potts statistical models of protein covariation

HIVE Center researchers explore how the characteristics of a data set effect the results of Potts covariation analysis.

Haldane A, Levy RM. Phys Rev E 99:032405 (2019). 

PubMed PMID: 30999494

PubMed Central PMCID: PMC6508952

Strain-specific effect on biphasic DNA binding by HIV-1 integrase

HIV-1 integrase binds to DNA in high-affinity and low-affinity modes.

Hill KJ, Rogers LC, Njenda DT, Burke DH, Sarafianos SG, Sönnerborg A, Neogi U, Singh K. AIDS 33, 588-592 (2019).

PubMed PMID: 30475264

PubMedCentral PMCID: PMC6472922

Bacterial glycosyltransferase-mediated cell-surface chemoenzymatic glycan modification

New chemoenzymatic methods are developed for modifying glycans, to explore glycan-mediated entry of viruses.

Hong S, Shi Y, Wu NC, Grande G, Douthit L, Wang H, Zhou W, Sharpless KB, Wilson IA, Xie J, Wu P. Nat Commun. 2019 10(1):1799.

PubMed PMID: 30996301

PubMedCentral PMCID: PMC6470217

Role of host tRNAs and aminoacyl-tRNA synthetases in retroviral replication

Transfer RNA plays key roles in the life cycle of retroviruses.

Jin D, Musier-Forsyth K. J Biol Chem. 294, 5352-5364 (2019).

PubMed PMID: 30700559

PubMedCentral PMCID: PMC6462514

HIV-1 integrase tetramers are the antiviral target of pyridine-based allosteric integrase inhibitors

Visualization of positive and negative sense viral RNA for probing the mechanism of direct-acting antivirals against hepatitis C virus

New methods reveal the distribution of positive-strand and negative-strand viral RNA in living cells.

Liu D, Tedbury PR, Lan S, Huber AD, Puray-Chavez MN, Ji J, Michailidis E, Saeed M, Ndongwe TP, Bassit LC, Schinazi RF, Ralston R, Rice CM, Sarafianos SG. Viruses. 2019 11(11). pii: E1039.

PubMed PMID: 31717338

PubMedCentral PMCID: PMC6893808

Challenges and opportunities in cryo-EM single-particle analysis

Cryoelectron microscopy is providing new opportunities for discovery and exploration of biomolecular structure.

Lyumkis D. J Biol Chem. 294, 5181-5197 (2019).

PubMed PMID: 30804214

PubMedCentral PMCID: PMC6442032

Resveratrol trimer enhances gene delivery to hematopoietic stem cells by reducing antiviral restriction at endosomes

Determining 3′-termini and sequences of nascent single-stranded viral DNA molecules during HIV-1 reverse transcription in infected cells

New methods for monitoring of nucleic acid intermediates during virus replication are presented

Pollpeter D, Sobala A, Malim MH. J Vis Exp. 2019 Jan 30;(143):10.3791/58715.

PubMed PMID: 30774124

PubMedCentral PMCID: PMC6682491

Structural studies and biological evaluation of T30695 variants modified with single chiral glycerol-T reveal the importance of LEDGF/p75 for the aptamer anti-HIV-integrase activities

HIV-1 Vif triggers cell cycle arrest by degrading cellular PPP2R5 phospho-regulators

HIV-1 stops infected cells from dividing by degrading regulatory proteins with the accessory protein Vif

Salamango DJ, Ikeda T, Moghadasi SA, Wang J, McCann JL, Serebrenik AA, Ebrahimi D, Jarvis MC, Brown WL, Harris RS. Cell Rep. 2019 Oct 29;29(5):1057-1065.e4.

PubMed PMID: 31665623

PubMedCentral PMCID: PMC6903395

D3R Grand Challenge 4: prospective pose prediction of BACE1 ligands with AutoDock-GPU

Conformational Changes in HIV-1 Reverse Transcriptase that Facilitate Its Maturation

The surprising role of transfer RNA in the maturation of HIV-1 reverse transcriptase is explored.

Slack RL, Ilina TV, Xi Z, Giacobbi NS, Kawai G, Parniak MA, Sarafianos SG, Sluis Cremer N, Ishima R. Structure. 2019 Oct 1;27(10):1581-1593.

PubMed PMID: 31471129

PubMedCentral PMCID: PMC6774901

An Isoquinoline Scaffold as a Novel Class of Allosteric HIV-1 Integrase Inhibitors

Massive-Scale Binding Free Energy Simulations of HIV Integrase Complexes Using Asynchronous Replica Exchange Framework Implemented on the IBM WCG Distributed Network

Very large computational screens of HIV integrase inhibitorsNew are performed using distributed computing.

Xia J, Flynn W, Gallicchio E, Uplinger K, Armstrong JD, Forli S, Olson AJ, Levy RM. J Chem Inf Model. 59, 1382-1397 (2019).

PubMed PMID: 30758197

PubMedCentral PMCID: PMC6496938

Structure-guided design of immunomodulatory RNAs specifically targeting the cytoplasmic viral RNA sensor RIG-I

RNA molecules are tuned for activity against a potential target for vaccination and immunotherapy.

Yong HY, Zheng J, Ho VCY, Nguyen MT, Fink K, Griffin PR, Luo D. FEBS Lett. 2019 593(21):3003-3014.

PubMed PMID: 31369683

Analysis of discrete local variability and structural covariance in macromolecular assemblies using Cryo-EM and focused classification

Focused classification is shown to be a powerful method for determining structures of flexible biomolecules.

Zhang C, Cantara W, Jeon Y, Musier-Forsyth K, Grigorieff N, Lyumkis D. Ultramicroscopy 203,170-180 (2019).

PubMed PMID: 30528101

PubMedCentral PMCID: PMC6476647

SuFEx-enabled, agnostic discovery of covalent inhibitors of human neutrophil elastase