Human immunodeficiency virus type 1 (HIV-1) genetic variation is high among virus populations and is of importance clinically for both drug resistance and vaccine development. A high rate of HIV mutation along with a high turnover rate of infected cells drives virus variation. This viral variation is thought to be responsible for the gradual breakdown of the immune system and is the mechanism of disease progression to AIDS. In the current application, we seek funding to continue studies began over a decade ago. We propose to examine the role of HIV mutation and its role on shaping replication capacity. We also propose to investigate these aspects of HIV-1 replication by analysis of reverse transcriptase mutants that alter virus variation relative to that of wt virus. We will explore how adaptive mutations can impact HIV-1 variation during the selection of new virus variants. We will determine whether the adaptive selection for altered replication capacity results in the selection of variant viruses. Lastly, we will investigate the origins of mutations in HIV-1 proviruses to determine mechanisms of virus variability.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-AARR-D (09))
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Janes, Daniel E
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University of Minnesota Twin Cities
Schools of Dentistry
United States
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Tabah, Azah A; Tardif, Keith; Mansky, Louis M (2014) Anti-HIV-1 activity of Trim 37. J Gen Virol 95:960-7
Dapp, Michael J; Bonnac, Laurent; Patterson, Steven E et al. (2014) Discovery of novel ribonucleoside analogs with activity against human immunodeficiency virus type 1. J Virol 88:354-63
Clouser, Christine L; Bonnac, Laurent; Mansky, Louis M et al. (2014) Characterization of permeability, stability and anti-HIV-1 activity of decitabine and gemcitabine divalerate prodrugs. Antivir Chem Chemother 23:223-30
Holtz, Colleen M; Mansky, Louis M (2013) Variation of HIV-1 mutation spectra among cell types. J Virol 87:5296-9
Dapp, Michael J; Patterson, Steven E; Mansky, Louis M (2013) Back to the future: revisiting HIV-1 lethal mutagenesis. Trends Microbiol 21:56-62
Holtz, Colleen M; Sadler, Holly A; Mansky, Louis M (2013) APOBEC3G cytosine deamination hotspots are defined by both sequence context and single-stranded DNA secondary structure. Nucleic Acids Res 41:6139-48
Dapp, Michael J; Heineman, Richard H; Mansky, Louis M (2013) Interrelationship between HIV-1 fitness and mutation rate. J Mol Biol 425:41-53
Rawson, Jonathan M; Heineman, Richard H; Beach, Lauren B et al. (2013) 5,6-Dihydro-5-aza-2'-deoxycytidine potentiates the anti-HIV-1 activity of ribonucleotide reductase inhibitors. Bioorg Med Chem 21:7222-8
Greggs 3rd, Willie M; Clouser, Christine L; Patterson, Steven E et al. (2012) Discovery of drugs that possess activity against feline leukemia virus. J Gen Virol 93:900-5
Dapp, Michael J; Holtz, Colleen M; Mansky, Louis M (2012) Concomitant lethal mutagenesis of human immunodeficiency virus type 1. J Mol Biol 419:158-70

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