Tracking the evolution of drug resistance for highly potent HIV protease inhibitors Project 2 - Swanstrom, UNC, Chapel Hill HIV-1 protease inhibitors are unique among all HIV-1 inhibitors in that they are transition state analogs which allows for binding constants that are orders of magnitude greater than any other type of inhibitor. Resistance to any inhibitor reflects the sequential addition of single amino acid changes that allow sufficient replication and resistance to the inhibitor to favor replication over the wild type virus in the presence of the inhibitor. However, if the resistance contribution of the mutation is too low to confer a growth advantage at the given level of drug compared to the wild type then resistance will not evolve. Also, potent inhibitors can restrict replication to such an extent that the evolution of resistance is slowed or even stopped. Protease inhibitors, because of their tight binding properties, offer the only possible inhibitor that can be envisioned to be able to avoid resistance and to drive (or maintain) the population at levels of negligible replication as a single agent. For this reason we propose this proof-of-concept study to explore the nature of resistance to these very tight-binding inhibitors using three approaches to identifying resistance mutations: selection of virus for resistance in expanded cell culture conditions;selection of virus for resistance in a humanized mouse model;and screening of large, genetically complex populations of protease expressed in yeast in the presence of protease inhibitors. We will also determine if these very tight binding inhibitors are able to suppress viral replication in the humanized mouse model as single agents. Finally, we will examine the role of mutations outside of the protease, in Gag, RT/IN, and gp41 to determine if there are mutations that affect fitness beyond the known mutations in the protease cleavage site.

Public Health Relevance

Tracking the evolution of drug resistance for highly potent HIV protease inhibitors Project 2 - Swanstrom, UNC, Chapel Hill Project 2 Subcontract - Bolon, UMASS Medical School Project 2 Subcontract - Luban, UMASS Medical School The selection for drug resistance is highly informative as to the pathways and mechanisms of resistance. We will examine the evolution of patterns of resistance to potent HIV-1 protease inhibitors to shed light on the underlying resistance mechanisms.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
United States
Zip Code
Leidner, Florian; Kurt Yilmaz, Nese; Paulsen, Janet et al. (2018) Hydration Structure and Dynamics of Inhibitor-Bound HIV-1 Protease. J Chem Theory Comput 14:2784-2796
Nemmara, Venkatesh V; Subramanian, Venkataraman; Muth, Aaron et al. (2018) The Development of Benzimidazole-Based Clickable Probes for the Efficient Labeling of Cellular Protein Arginine Deiminases (PADs). ACS Chem Biol 13:712-722
Ilina, Tatiana V; Slack, Ryan L; Elder, John H et al. (2018) Effect of tRNA on the Maturation of HIV-1 Reverse Transcriptase. J Mol Biol 430:1891-1900
Khan, Shahid N; Persons, John D; Paulsen, Janet L et al. (2018) Probing Structural Changes among Analogous Inhibitor-Bound Forms of HIV-1 Protease and a Drug-Resistant Mutant in Solution by Nuclear Magnetic Resonance. Biochemistry 57:1652-1662
Persons, John D; Khan, Shahid N; Ishima, Rieko (2018) An NMR strategy to detect conformational differences in a protein complexed with highly analogous inhibitors in solution. Methods 148:9-18
Potempa, Marc; Lee, Sook-Kyung; Kurt Yilmaz, Nese et al. (2018) HIV-1 Protease Uses Bi-Specific S2/S2' Subsites to Optimize Cleavage of Two Classes of Target Sites. J Mol Biol 430:5182-5195
Tilvawala, Ronak; Nguyen, Son Hong; Maurais, Aaron J et al. (2018) The Rheumatoid Arthritis-Associated Citrullinome. Cell Chem Biol 25:691-704.e6
Venev, Sergey V; Zeldovich, Konstantin B (2018) Thermophilic Adaptation in Prokaryotes Is Constrained by Metabolic Costs of Proteostasis. Mol Biol Evol 35:211-224
Wong, Alicia; Bryzek, Danuta; Dobosz, Ewelina et al. (2018) A Novel Biological Role for Peptidyl-Arginine Deiminases: Citrullination of Cathelicidin LL-37 Controls the Immunostimulatory Potential of Cell-Free DNA. J Immunol 200:2327-2340
Sun, Bo; Dwivedi, Nishant; Bechtel, Tyler J et al. (2017) Citrullination of NF-?B p65 promotes its nuclear localization and TLR-induced expression of IL-1? and TNF?. Sci Immunol 2:

Showing the most recent 10 out of 22 publications