2021 Publications

Evaluating local and directional resolution of cryo-EM density maps

Methods are presented for evaluating and improving cryo-EM maps.

Aiyer S, Zhang C, Baldwin PR, Lyumkis D. Methods Mol Biol. 2021;2215:161-187.

PubMed PMID: 33368004

Tools for visualizing and analyzing Fourier space sampling in Cryo-EM

Tools are presented for understanding how molecular orientation impacts structure determination by cryoelectron microscopy.

Baldwin PR, Lyumkis D. Prog Biophys Mol Biol. 2021 Mar;160:53-65.

PubMed PMID: 32645314

PubMedCentral PMCID: PMC7785567

rigrag: high-resolution mapping of genic targeting preferences during HIV-1 integration in vitro and in vivo

A method is presented for identifying genes that are recurrently targeted by HIV integrase, and genes that are recurrently avoided.

Bedwell GJ, Jang S, Li W, Singh PK, Engelman AN. Nucleic Acids Res. 2021 Jul 21;49(13):7330-7346.

PubMed PMID: 34165568

PubMedCentral PMCID: PMC8287940

MX2-mediated innate immunity against HIV-1 is regulated by serine phosphorylation

Several cellular proteins are identified that interact with MX2 as part of its antiviral action.

Betancor G, Jimenez-Guardeño JM, Lynham S, Antrobus R, Khan H, Sobala A, Dicks MDJ, Malim MH. Nat Microbiol. 2021 Aug;6(8):1031-1042. Erratum in: Nat Microbiol. 2021 Sep;6(9):1211.

PubMed PMID: 34282309

PubMedCentral PMCID: PMC7611661 

Drugs that inhibit TMEM16 proteins block SARS-CoV-2 spike-induced syncytia

Three thousand approved drugs are screened for use in COVID-19 therapy.

Braga L, Ali H, Secco I, Chiavacci E, Neves G, Goldhill D, Penn R, Jimenez-Guardeño JM, Ortega-Prieto AM, Bussani R, Cannatà A, Rizzari G, Collesi C, Schneider E, Arosio D, Shah AM, Barclay WS, Malim MH, Burrone J, Giacca M.  Nature. 2021 Jun;594(7861):88-93.

PubMed PMID: 33827113

PubMedCentral PMCID: PMC7611055

Avoiding drug resistance in HIV reverse transcriptase

HIVE Center researchers review the biology of HIV reverse transcriptase and discuss approaches to fight drug resistance.

Cilento ME, Kirby KA, Sarafianos SG.  Chem Rev. 2021 Mar 24;121(6):3271-3296.

PubMed PMID: 33507067

PubMedCentral PMCID: PMC8149104 

Revealing the structural plasticity of SARS-CoV-2 nsp7 and nsp8 using structural proteomics

Solution-based structural proteomics techniques reveal that two coronavirus non-structural proteins may form multiple oligomeric states.

Courouble VV, Dey SK, Yadav R, Timm J, Harrison JJEK, Ruiz FX, Arnold E, Griffin PR. J Am Soc Mass Spectrom. 2021 Jul 7;32(7):1618-1630.

PubMed PMID: 34121407

PubMedCentral PMCID: PMC8231661

Discrimination between functional and non-functional cellular Gag complexes involved in HIV-1 assembly

HIV Gag protein bound to cellular ribosomes may acts a reservoir of Gag during assembly of new viruses

Deng Y, Hammond JA, Pauszek R, Ozog S, Chai I, Rabuck-Gibbons J, Lamichhane R, Henderson SC, Millar DP, Torbett BE, Williamson JR.  J Mol Biol. 2021 Apr 16;433(8):166842.

PubMed PMID: 33539875

The SMC5/6 complex compacts and silences unintegrated HIV-1 DNA and is antagonized by Vpr

Researchers explore how HIV protein Vpr blocks the natural defenses against integration of the viral genome.

Dupont L, Bloor S, Williamson JC, Cuesta SM, Shah R, Teixeira-Silva A, Naamati A, Greenwood EJD, Sarafianos SG, Matheson NJ, Lehner PJ. Cell Host Microbe. 2021 May 12;29(5):792-805.

PubMed PMID: 33811831

PubMedCentral PMCID: PMC8118623

Neutralizing antibody activity in convalescent sera from infection in humans with SARS-CoV-2 and variants of concern

Individuals infected with different strains of SARS-CoV-2 produce cross-neutralizing antibodies, but they many not be as effective against divergent lineages of the virus.

Dupont L, Snell LB, Graham C, Seow J, Merrick B, Lechmere T, Maguire TJA, Hallett SR, Pickering S, Charalampous T, Alcolea-Medina A, Huettner I, Jimenez-Guardeño JM, Acors S, Almeida N, Cox D, Dickenson RE, Galao RP, Kouphou N, Lista MJ, Ortega-Prieto AM, Wilson H, Winstone H, Fairhead C, Su JZ, Nebbia G, Batra R, Neil S, Shankar-Hari M, Edgeworth JD, Malim MH, Doores KJ. Nat Microbiol. 2021 Nov;6(11):1433-1442.

PubMed PMID: 34654917

PubMedCentral PMCID: PMC8556155

Mechanistic roles of tyrosine phosphorylation in reversible amyloids, autoinhibition, and endosomal membrane association of ALIX

An autoinhibition mechanism relocates ALIX to the cytosol and tyrosine phosphorylation plays many roles in its functions.

Elias RD, Ramaraju B, Deshmukh L. J Biol Chem. 2021 Nov;297(5):101328.

PubMed PMID: 34688656

PubMedCentral PMCID: PMC8577116

MrHAMER yields highly accurate single molecule viral sequences enabling analysis of intra-host evolution

A new nanopore-based method allows long-range sequencing of thousands of viral genomes from clinical samples.

Gallardo CM, Wang S, Montiel-Garcia DJ, Little SJ, Smith DM, Routh AL, Torbett BE.  Nucleic Acids Res. 2021 Jul 9;49(12):e70.

PubMed PMID: 33849057

PubMedCentral PMCID: PMC8266615

Neutralization potency of monoclonal antibodies recognizing dominant and subdominant epitopes on SARS-CoV-2 Spike is impacted by the B.1.1.7 variant

A panel of over a hundred antibodies are used to explore how SARS-CoV-2 evades neutralization by the immune system.

Graham C, Seow J, Huettner I, Khan H, Kouphou N, Acors S, Winstone H, Pickering S, Galao RP, Dupont L, Lista MJ, Jimenez-Guardeño JM, Laing AG, Wu Y, Joseph M, Muir L, van Gils MJ, Ng WM, Duyvesteyn HME, Zhao Y, Bowden TA, Shankar-Hari M, Rosa A, Cherepanov P, McCoy LE, Hayday AC, Neil SJD, Malim MH, Doores KJ.  Immunity. 2021 Jun 8;54(6):1276-1289.e6. doi: 10.1016/j.immuni.2021.03.023.

PubMed PMID: 33836142

PubMedCentral PMCID: PMC8015430

Mi3-GPU: MCMC-based Inverse Ising Inference on GPUs for protein covariation analysis

HIVE Center members improve methods for predicting interactions between amino acids based on observed mutational covariations.

Haldane A, Levy RM. Comput Phys Commun. 2021 Mar;260:107312.

PubMed PMID: 33716309

PubMedCentral PMCID: PMC7944406 

Crystal structure of a retroviral polyprotein: Prototype foamy virus protease-reverse transcriptase (PR-RT)

The structure of a monomeric precursor of PFV protease-reverse transcriptase is presented.

Harrison JJEK, Tuske S, Das K, Ruiz FX, Bauman JD, Boyer PL, DeStefano JJ, Hughes SH, Arnold E. Viruses. 2021 Jul 29;13(8):1495. doi: 10.3390/v13081495.

PubMed PMID: 34452360

PubMedCentral PMCID: PMC8402755

Icosahedral virus structures and the Protein Data Bank

The history of structural studies of icosahedral viruses is reviewed.

Johnson JE, Olson AJ.  J Biol Chem. 2021 Jan-Jun;296:100554.

PubMed PMID: 33744290

PubMedCentral PMCID: PMC8081926

TMPRSS2 promotes SARS-CoV-2 evasion from NCOA7-mediated restriction

Evidence is found that SARS-CoV-2 enters cells by two different pathways as a way to avoid restriction.

Khan H, Winstone H, Jimenez-Guardeño JM, Graham C, Doores KJ, Goujon C, Matthews DA, Davidson AD, Rihn SJ, Palmarini M, Neil SJD, Malim MH. PLoS Pathog. 2021 Nov 22;17(11):e1009820. doi: 10.1371/journal.ppat.1009820.

PubMed PMID: 34807954

PubMedCentral PMCID: PMC8648102

Resilient SARS-CoV-2 diagnostics workflows including viral heat inactivation

Commercially-available methods for detection of SARS-CoV-2 nucleic acid are compared.

Lista MJ, Matos PM, Maguire TJA, Poulton K, Ortiz-Zapater E, Page R, Sertkaya H, Ortega-Prieto AM, Scourfield E, O’Byrne AM, Bouton C, Dickenson RE, Ficarelli M, Jimenez-Guardeño JM, Howard M, Betancor G, Galao RP, Pickering S, Signell AW, Wilson H, Cliff P, Kia Ik MT, Patel A, MacMahon E, Cunningham E, Doores K, Agromayor M, Martin-Serrano J, Perucha E, Mischo HE, Shankar-Hari M, Batra R, Edgeworth J, Zuckerman M, Malim MH, Neil S, Martinez-Nunez RT. PLoS One. 2021 Sep 15;16(9):e0256813.

PubMed PMID: 34525109

PubMedCentral PMCID: PMC8443028

HIV-1 integrase binding to genomic RNA 5′-UTR induces local structural changes in vitro and in virio

HIVE Center researchers find that nucleocapsid and integrase bind differently to HIV genomic RNA

Liu S, Koneru PC, Li W, Pathirage C, Engelman AN, Kvaratskhelia M, Musier-Forsyth K. Retrovirology. 2021 Nov 22;18(1):37.

PubMed PMID: 34809662

PubMedCentral PMCID: PMC8609798

Rotten to the core: antivirals targeting the HIV-1 capsid core

The role of HIV-1 capsid in the viral life cycle and the mechanisms of capsid inhibitors are reviewed.

McFadden WM, Snyder AA, Kirby KA, Tedbury PR, Raj M, Wang Z, Sarafianos SG. Retrovirology. 2021 Dec 22;18(1):41. doi: 10.1186/s12977-021-00583-z.

PubMed PMID: 34937567

PubMedCentral PMCID: PMC8693499

The generative capacity of probabilistic protein sequence models

Several methods for predicting evolutionary sequence covariation in viral populations are tested and compared.

McGee F, Hauri S, Novinger Q, Vucetic S, Levy RM, Carnevale V, Haldane A. Nat Commun. 2021 Nov 2;12(1):6302.

PMID: 34728624

PMCID: PMC8563988

Selective packaging of HIV-1 RNA genome is guided by the stability of 5′ untranslated region polyA stem

The stability of the polyA stem guides selective packaging of different forms of the HIV-1 genomic RNA.

Nikolaitchik OA, Liu S, Kitzrow JP, Liu Y, Rawson JMO, Shakya S, Cheng Z, Pathak VK, Hu WS, Musier-Forsyth K. Proc Natl Acad Sci U S A. 2021 Dec 14;118(50):e2114494118. doi: 10.1073/pnas.2114494118.

PubMed PMID: 34873042

PubMedCentral PMCID: PMC8685901

Retroviral integrase: Structure, mechanism, and inhibition

The function, structure, and inhibition of retroviral integrases are reviewed.

Passos DO, Li M, Craigie R, Lyumkis D. Enzymes. 2021;50:249-300. doi: 10.1016/bs.enz.2021.06.007. Epub 2021 Aug 23.

PubMed PMID: 34861940

PubMedCentral PMCID: PMC8732146

Quantitative NMR study of insulin-degrading enzyme using amyloid-β and HIV-1 p6 elucidates its chaperone activity

Insulin-degrading enzyme forms a single productive complex with HIV p6 and a more complex set of interactions with amyloids.

Ramaraju B, Nelson SL, Zheng W, Ghirlando R, Deshmukh L. Biochemistry. 2021 Aug 24;60(33):2519-2523.

PubMedCentral PubMed PMID: 34342986

Sec24C is an HIV-1 host dependency factor crucial for virus replication

Cellular protein Sec24C plays essential roles in the trafficking of HIV-1.

Rebensburg SV, Wei G, Larue RC, Lindenberger J, Francis AC, Annamalai AS, Morrison J, Shkriabai N, Huang SW, KewalRamani V, Poeschla EM, Melikyan GB, Kvaratskhelia M. Nat Microbiol. 2021 Mar 1. doi: 10.1038/s41564-021-00868-1. Epub ahead of print.

PubMed PMID: 33649557

PubMedCentral PMCID: PMC8012256

Integrase strand transfer inhibitors are effective anti-HIV drugs

HIV Center members and collaborators review the current stated of clinically-relevant integrase strand transfer inhibitors.

Smith SJ, Zhao XZ, Passos DO, Lyumkis D, Burke TR Jr, Hughes SH. Integrase Strand Transfer Inhibitors Are Effective Anti-HIV Drugs. Viruses. 2021 Jan 29;13(2):205.

PubMed PMID: 33572956

PubMedCentral PMCID: PMC7912079

HIV-1 integrase inhibitors with modifications that affect their potencies against drug resistant integrase mutants

Based on structures of HIV-1 and SIV integrases, new integrase strand transfer inhibitors are designed and tested for their ability to block drug-resistant mutants of the enzyme.

Smith SJ, Zhao XZ, Passos DO, Pye VE, Cherepanov P, Lyumkis D, Burke TR Jr, Hughes SH. ACS Infect Dis. 2021 Jun 11;7(6):1469-1482.

PubMed PMID: 33686850

PubMedCentral PMCID: PMC8205226

Molecular dynamics free energy simulations reveal the mechanism for the antiviral resistance of the M66I HIV-1 capsid mutation

The free energy cost of protein side chain reorganization is largely responsible for drug resistance of a capsid inhibitor.

Sun Q, Levy RM, Kirby KA, Wang Z, Sarafianos SG, Deng N.  Viruses. 2021 May 15;13(5):920.

PMID: 34063519

PMCID: PMC8156065

Computational design of small molecular modulators of protein-protein interactions with a novel thermodynamic cycle: Allosteric inhibitors of HIV-1 integrase

A new method for targeting protein-protein interfaces is applied to design of integrase inhibitors

Sun Q, Ramaswamy VSK, Levy R, Deng N. Protein Sci. 2021 Feb;30(2):438-447.

PubMed PMID: 33244804

PubMedCentral PMCID: PMC7784772

Cleavage and Polyadenylation Specificity Factor 6 is required for efficient HIV-1 latency reversal

The cellular protein CPSF6 plays a novel role in HIV-1 transcription and latency of the virus.

Zheng Y, Schubert HL, Singh PK, Martins LJ, Engelman AN, D’Orso I, Hill CP, Planelles V.  mBio. 2021 Jun 29;12(3):e0109821.

PubMed PMID: 34154414

Interactions of HIV-1 Capsid with host factors and their implications for developing novel therapeutics

The structure and function of HIV-1 capsid and its interactions with host factors and drugs are reviewed.

Zhuang S, Torbett BE. Viruses. 2021 Mar 5;13(3):417.

PubMed PMID: 33807824

PubMedCentral PMCID: PMC8001122