Louis M. Mansky, Ph.D.
Departments of Microbiology and Diagnostic and Biological Sciences
Institute for Molecular Virology
Iowa State University, Ph.D.
Cell and molecular biology of HIV and HTLV; Antiviral drug target identification; Antiviral drug resistance; HIV genetic variation, evolution and population genetics; Viral quasispecies; Virus assembly; Evolution of emerging viruses; Paleovirology
The study of retroviruses over the past three decades has led to some of the most important discoveries in biomedical research, and has laid the foundation for biotechnology, cancer research, AIDS research, and human gene therapy. The discovery of reverse transcriptase helped to create the biotechnology industry, the discovery of oncogenes helped to advance our understanding of the genetic basis of cancer, and the discovery of retroviruses in higher animals led to the discovery of human retroviruses that cause cancer (HTLV-1) and AIDS (HIV-1). The creation of retroviral vectors and retrovirus helper cell lines helped to establish the field of gene therapy.
Retroviruses are relatively simple viruses that encode from three to ten genes, but are unusual in that they undergo a step in their life cycle called reverse transcription, which is the synthesis of double-stranded DNA from single-stranded RNA. We are exploring the accuracy of this process in HIV-1 replication and how it influences not only the evolution of HIV-1 variants that are resistant to anti-HIV-1 drugs, but also how it influences the development of an effective AIDS vaccine. We are also exploring how the APOBEC3 proteins impact HIV evolution and drug resistance. A long-term goal of our efforts is to define the molecular determinants for HIV-1 mutation in order to 1) manipulate HIV-1 evolution and improve the efficacy of anti-HIV-1 drugs, and 2) provide the basis for new intervention strategies.
Central steps in the retrovirus life cycle include the recognition of the genomic RNA by the Gag protein, trafficking of Gag and viral RNA to the plasma membrane, Gag oligomerization, and ultimately the biogenesis of virus particles. The details behind how Gag and RNA trafficking as well as virus particle biogenesis occurs is currently being investigated via collaboration by employing highly sophisticated biophysical approaches - including fluorescence spectroscopy methodologies that have single molecule resolution as well as cryoelectron microscopy/tomography. A long term goal of these studies is to develop a better understanding of the detailed steps of Gag oligomerization, viral RNA packaging, and virus biogenesis/virus structure. Such information will ultimately be useful for the discovery of new targets for the rational design of antiviral drugs.
Metabolic disorders associated with highly active antiretroviral therapy (HAART) are becoming increasingly important in the chronically HIV-infected population that has access to therapy. Clinical observations have revealed a strong correlation between bone density loss in HIV-infected individuals during HAART, particularly in conjunction with the antiretroviral drug tenofovir - a nucleotide analog that inhibits HIV reverse transcriptase. We are working collaboratively with bone biologists and AIDS clinicians to investigate how HIV-1 infection and tenofovir can cause bone mineral density loss.
Institute for Molecular Virology
Selected Recent Publications:
- Fogarty KH, Berk S, Grigsby IF, Chen Y, Mansky LM, Mueller JD. 2013. Interrelationship between cytoplasmic retroviral Gag concentration and Gag-membrane association. Journal of Molecular Biology. Epub ahead of print.
- Sun M, Grigsby IF, Gorelick RJ, Mansky LM, Musier-Forsyth K. 2013. Retrovirus-specific differences in matrix and nucleocapsid protein-nucleic acid interactions: implications for genomic RNA packaging. Journal of Virology. Epub ahead of print.
- Dapp MJ, Bonnac, L, Patterson, SE, Mansky, LM. 2013. Discovery of novel ribonucleoside analogs with activity against human immunodeficiency virus type 1. Journal of Virology. Epub ahead of print.
- Clouser, CL, Bonnac, L, Mansky, LM, Patterson, SE. 2013. Characterization of permeability, stability, and anti-HIV-1 activity of decitabine and gemcitabine divalerate prodrugs. Antiviral Chemistry & Chemotherapy. Epub ahead of print.
- Rawson, JM, Heineman, RH, Beach, LB, Martin, JL, Schnettler, EK, Dapp, MJ, Patterson, SE, Mansky, LM. 2013. 5,6-Dihydro-5-aza-2'-deoxycytidine potentiates the anti-HIV-1 activity of ribonucleotide reductase inhibitors.Bioorg Med Chem. Nov 15;21(22):7222-8.
- Bonnac, LF, Mansky, LM, Patterson, SE. 2013. Structure-activity relationships and design of viral mutagens and application to lethal mutagenesis. Journal of Medicinal Chemistry. Epub ahead of print
- Holtz CM, Sadler HA and Mansky LM. 2013. APOBEC3G cytosine deamination hotspots are defined by both sequence context and single-stranded DNA secondary structure. Nucleic Acids Research 41:6139-6148.
- Holtz CM, Mansky LM. 2013. Variation of HIV-1 mutation spectra among cell types. J Virol. Epub ahead of print
- Dapp MJ, Patterson, SE, Mansky, LM. 2012. Back to the future: revisiting HIV-1 lethal mutagenesis. Trends in Microbiology. 21:56-62.
- Dapp MJ, Heineman, RH, Mansky LM. 2012. Interrelationship between HIV-1 fitness and mutation rate. J Mol Biol. 425:41-53.
- Clouser, CL, Chauhan, J, Bess, MA, Oploo, JL, Zhou, D, Dimick-Gray, S, Mansky, LM, Patterson, SE. 2012. Anti-HIV-1 activity of resveratrol derivatives and synergistic inhibition of HIV-1 by the combination of resveratrol and decitabine. Bioorg Med Chem Lett. 22:6642-6646.
- Dapp MJ, Holtz CM, Mansky LM. 2012. Concomitant lethal mutagenesis of human immunodeficiency virus type 1. J Mol Biol. 419:158-170.
- Clouser CL, Holtz CM, Mullet M, Crankshaw DL, Briggs JE, O’Sullivan MG,
Patterson SE, Mansky LM. 2012. Activity of a novel combined antiretroviral
therapy of gemcitabine and decitabine in a mouse model for HIV-1.
Antimicrobial Agents and Chemotherapy. 56:1942-1948.
- Greggs, WM 3rd, Clouser CL, Patterson SE, Mansky LM. 2012. Discovery of
drugs that possess activity against feline leukemia virus. Journal of
General Virology 93:900-905.
- Guenzel CA, Hérate C, Le Rouzic E, Maidou-Peindara P, Sadler HA, Rouyez
MC, Mansky LM, Benichou S. 2012. Recruitment of the nuclear form of uracil DNA glycosylase into virus particles participates in the full infectivity of HIV-1. J Virol. 86:2533-44.
- Wu K, Chen L, Peng G, Zhou W, Pennell CA, Mansky LM, Geraghty RJ, Li F.
2011. A virus-binding hot spot on human angiotensin-converting enzyme 2 is
critical for binding of two different coronaviruses J Virol. 2011
- Fogarty, KH, Zhang, W, Grigsby, IF, Johnson, J, Chen, Y, Mueller, JD and LM Mansky. 2011. New insights into HTLV-1 particle structure, assembly and
Gag-Gag interactions in living cells. Viruses 3(6):770-93.
- Fogarty, K.H., Johnson, J.L., Grigsby, I.F., MacDonald, P.J., Smith, E.M., Chen, Y., Rawson, J.M., Mansky, L.M., and J.D. Mueller. 2011. Characterization of cytoplasmic Gag-Gag interactions by dual-color z-scan fluorescence fluctuation spectroscopy. Biophysical Journal 100:1587-1595.
- Greggs, W.M., Clouser, C.L., Patterson, S.E., and L.M. Mansky. 2011. Broadening the use of antiretroviral therapy: the case for feline leukemia virus. Therapeutics and Clinical Risk Management 7:115 – 122.
- Clouser, C.L., Holtz, C.M., Mullet, M., Crankshaw, D.L., Briggs, J.E., Chauhan, J., Patterson, S.E., and L.M. Mansky. 2011. Analysis of the ex vivo and in vivo antiretroviral activity of gemcitabine. PLoS One 6:e15840
- Ni, Z., Knorr, D.A., Clouser, C.L., Hexum, M.K., Souther, P., Mansky, L.M., Park, I.-H., and D.S. Kaufman. 2011. Human pluripotent stem cells produce natural killer cells that mediate anti-HIV-1 activity utilizing diverse cellular mechanisms. Journal of Virology 85:43-50