2015 Research Highlights

The Future of HIV-1 Therapeutics: Resistance is Futile?

Alpha-carboxy nucleoside phosphonates as universal nucleoside triphosphate mimics

Distinguishing Binders from False Positives by Free Energy Calculations: Fragment Screening against the Flap Site of HIV Protease

Deep Sequencing of Protease Inhibitor Resistant HIV Patient Isolates Reveals Patterns of Correlated Mutations in Gag and Protease

Deep sequencing of viruses from 93 patients has revealed mutations in Gag proteins contribute to recurrent treatment failure.

Flynn WF, Chang MW, Tan Z, Oliveira G, Yuan J, Okulicz JF, Torbett BE, Levy RM. PLoS Comput Biol. 11, e1004249 (2015).

PubMed PMID: 25894830

PubMed Central PMCID: PMC4404092

Distribution and redistribution of HIV-1 nucleocapsid in immature, mature, and integrase-inhibited virions: a role for integrase in maturation

An important role of integrase in packaging of the HIV-1 genome is revealed.

Fontana J, Jurado KA, Cheng N, Ly NL, Fuchs JR, Gorelick RJ, Engelman AN & Steven AC. J. Virol. 89, 9765-9780 (2015).

PubMed PMID: 26178982

PubMed Central PMCID: PMC4577894

Asynchronous replica exchange software for grid and heterogenous computing

Methods for performing molecular dynamics simulations on large clusters of computers are presented.

Gallicchio E, Xia J, Flynn WF, Zhang B, Samlalsingh S, Mentes A & Levy RM. Comp. Phys. Commun. 196, 236-246 (2015)

PubMed PMID: 27103749

PubMed Central PMCID: PMC4834714

Differential isotopic enrichment to facilitate characterization of asymmetric multimeric proteins using hydrogen/deuterium exchange mass spectrometry

By labeling the two subunits of reverse transcriptase with different isotopes of nitrogen, the subunits may be distinguished in hydrogen/deuterium exchange experiments.

Goswami D, Tuske S, Pascal BD, Bauman JD, Patel D, Arnold E, Griffin PR. Anal Chem 87, 4015-22 (2015).

PubMed PMID: 25763479

PubMedCentral PMCID: PMC4445842

X-ray structures of native HIV-1 capsid protein reveal conformational variability

Pronounced inhibition shift from HIV reverse transcriptase to herpetic DNA polymerases by increasing the flexibility of alpha-carboxy nucleotide phosphates.

A new class of polymerase inhibitors is tuned to target different viruses.

John J, Kim Y, Bennett N, Das K, Liekens S, Naesens L, Arnold E, Maguire AR, Gotte M, Dehaen W & Balzarini J. J Med Chem 58, 8110-8127 (2015)

PubMed PMID: 26450273

PubMed Central PMCID: PMC4893804

CellPACK: A Virtual Mesoscope to Model and Visualize Structural Systems Biology

A new method for creating 3D models of cellular systems is applied to the analysis of envelope glycoprotein distribution in HIV.

Johnson, G. T., Autin, L., Al-Alusi, M., Goodsell, D. S., Sanner, M. F., and Olson, A. J., Nat Methods 12, 85-91 (2015).

Pubmed PMID: 25437435

PubMedCentral PMCID: PMC4281296

HCV glycoprotein structures: what to expect from the unexpected

Recent structural insights into the envelope glycoproteins of hepatitis C virus are reviewed.

Khan AG, Miller MT, Marcotrigiano J Curr Opin Virol 12, 53-58 (2015).

PubMed PMID: 25790756

PubMedCentral PMCID: PMC4505365

Structural basis of clade-specific HIV-1 neutralization by humanized anti-V3 monoclonal antibody KD-247

Fast hepatitis C virus RNA elimination and NS5A redistribution by NS5A inhibitors studied by multiplex assay approach

A new method is presented to assess the effectiveness of novel inhibitors of hepatitis C virus.

Liu D, Ji J, Ndongwe TP, Michallidis E, Rice CM, Ralston R & Sarafianos SG. Antimicrobial Agents Chemotherapy 59, 3482-3492 (2015)

PubMed PMID: 25845863

PubMed Central PMCID: PMC4432190

Synthesis and properties of 2′-deoxy-2′,4′-difluoroarabinose-modified nucleic acids

New structure sheds light on selective HIV-1 genomic RNA packaging

HIVE members review current work probing the structure and function of the HIV genome.

Olson ED, Cantara WA & Musier-Forsyth K. Viruses 7, 4826-4835 (2015)

PubMed PMID: 26305251

PubMed Center PMCID: PMC4576207

CoVaMa: Co-variation Mapper for disequilibrium analysis of mutant loci in viral populations using next-generation sequence data

A new method has been developed to analyze linked variations in large sequence datasets from viral populations.

Routh A, Chang MW, Okulicz JF, Johnson JE & Torbett BE. Methods 91, 40-47 (2015)

PubMed PMID: 26408523

PubMed Central PMCID: PMC4684750

Structural integrity of the ribonuclease H domain in HIV-1 reverse transcriptase

The role of several mutations in the folding of reverse transcriptase is revealed.

Slack RL, Spiriti J, Ahn J, Parniak MA, Zuckerman DM & Ishima R. Proteins Struct Funct Bioinform 83, 1526-1538 (2015)

PubMed PMID: 26061827

PubMed Central PMCID: PMC4509971

Design, synthesis, biochemical, and antiviral evaluations of C6 benzyl and C6 biarylmethyl substituted 2-hydroxylisoquinoline-1,3-diones: dual inhibition agains HIV reverse transcriptase-associated RNase H and polymerase with antiviral activities

Inhibitors that block the RNase H site of reverse transcriptase have been discovered.

Vernekar SKV, Liu Z, Nagy E, Miller L, Kirby KA, Wilson DJ, Kankanala J, Sarafianos SG, Parniak MA & Wang Z. J. Med. Chem. 58, 651-664 (2015).

PubMed PMID: 25522204

PubMedCentral PMCID: PMC4306517

Role of the mammalian target of rapamycin pathway in lentiviral vector transduction of hematopoietic stem cells

Rapamycin improves lentiviral delivery of genes to hematopoietic stem cells.

Wang CX & Torbett BE. Curr Opin Hematol 22, 302-308 (2015)

PubMed PMID: 26049750

PubMed Central PMCID: PMC4688901

Large-scale asynchronous and distributed multidimensional replical exchange molecular simulations and efficiency analysis

New methods are developed for rapid molecular dyamics simulations on large clusters of computers.

Xia J, Flynn WF, Gallicchio E, Zhang BW, He P, Tan Z & Levy RM. J Comput Chem 36, 1772-1785 (2015)

Pubmed PMID: 26149645

PubMed Central PMCID: PMC4512903