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Addressing the global HIV/AIDS epidemic: non-subtype B HIV-1 protease

Addressing the global HIV/AIDS epidemic: non-subtype B HIV-1 protease. C. Taylor Gilliland Mentor: Ben M. Dunn, Ph.D. Dept. of Biochemistry and Molecular Biology College of Medicine University of Florida. HIV/AIDS Epidemic Status. Source: 2006 Report on the Global AIDS Epidemic, UNAIDS, WHO.

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Addressing the global HIV/AIDS epidemic: non-subtype B HIV-1 protease

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  1. Addressing the global HIV/AIDS epidemic: non-subtype B HIV-1 protease • C. Taylor Gilliland • Mentor: Ben M. Dunn, Ph.D. • Dept. of Biochemistry and Molecular Biology • College of Medicine • University of Florida

  2. HIV/AIDS Epidemic Status Source: 2006 Report on the Global AIDS Epidemic, UNAIDS, WHO

  3. HIV/AIDS Epidemic Status Source: 2006 Report on the Global AIDS Epidemic, UNAIDS, WHO

  4. HIV Genetic Epidemiology Takebe et al. (2004) Pediatrics International. 46. 236-244.

  5. Geographic Distribution of HIV-1 Subtypes and RFs F B B C D A,AG BF C Spira et al. (2003) J of Antimicrobial Chemotherapy. 51. 229-340.

  6. Role of HIV-1 Protease 1MUI 1MUI

  7. Non-Subtype B HIV-1 Proteases Studied in Dunn Lab

  8. Clinically Approved HIV-1 Protease Inhibitors

  9. Methodology

  10. Inhibitor RTV IDV SQV NFV APV LPV ATV TPV Subtype Ki (nM) B (LAI) 0.7 ± 0.1 1.8 ± 0.1 1.7 ± 0.4 2.2 ± 0.3 0.4 ± 0.1 0.11 ± 0.03 0.07 ± 0.01 0.4 ± 0.04 C 0.27 ± 0.06 3.3 ± 0.3 2.7 ± 0.3 2.6 ± 0.2 0.29 ± 0.03 0.2 ± 0.02 0.13 ± 0.01 0.13 ± 0.03 A 0.25 ± 0.03 2.1 ± 0.2 0.80 ± 0.06 2.0 ± 0.3 0.26 ± 0.03 0.03 ± 0.01 0.10 ± 0.02 0.56 ± 0.04 H 0.18 ± 0.03 1.7 ± 0.2 0.65 ± 0.10 1.5 ± 0.2 0.35 ± 0.07 1.1 ± 0.26 0.03 ± 0.004 0.22 ± 0.04 D 0.18 ± 0.03 2.1 ± 0.2 2.1 ± 0.2 3.1 ± 0.4 0.35 ± 0.06 0.07 ± 0.02 0.05 ± 0.01 0.43 ± 0.07 AC P81S 1.5 ± 0.2 10.2 ± 0.4 18.7 ± 0.7 5.1 ± 0.9 0.79 ± 0.09 2.3 ± 1.1 0.54 ± 0.06 0.9 ± 0.1 CRF-BF 0.07 ± 0.02 1.7 ± 0.2 0.74 ± 0.08 1.3 ± 0.2 0.46 ± 0.08 0.1± 0.2 0.06 ± 0.01 0.56 ± 0.05 F 0.77 ± 0.05 3.1 ± 0.5 1.3 ± 0.3 0.48 ± 0.02 0.41 ± 0.04 1.0 ± 0.16 0.81 ± 0.07 Inhibition of HIV-1 Pr

  11. Relative Fold Change in Ki Values of Non-Subtype B Pr Relative Fold Change Inhibitor

  12. Inhibitor RTV IDV SQV NFV APV LPV ATV TPV Subtype Ki (nM) URF-AC 0.48 ± 0.1 0.97 ± 0.1 1.2 ± 0.3 0.51 ± 0.2 0.089 ± 0.02 0.15 ± 0.02 0.1 ± 0.06 URF-AC P81S 1.46 ± 0.2 10.23 ± 0.37 18.7 ± 0.7 5.08 ± 0.89 0.79 ± 0.09 2.3 ± 1.1 0.54 ± 0.06 0.9 ± 0.1 B P81S 2.7 ± 0.2 0.81 ± 0.04 1.2 ± 0.2 0.52 ± 0.06 0.25 ± 0.03 Effect of P81S Mutation in URF-AC and Subtype B B PQITLWQRPLVTIKIGGQLKEALLDTGADDTVLEEMSLPGRWKPKMIGGIGGFIKVRQYDQILIEICGHKAIGTVLVGPTPVNIIGRNLLTQIGCTLNF AC ------------V------R---------------IN---K---------------------------K-----------S-------M---------- Relative Fold Change Inhibitor

  13. Conclusions • - tight binding of inhibitors to all subtypes and recombinant forms • - effectiveness of tipranavir (TPV) • - P81S as possible secondary drug-resistance mutation • - continuing efforts to obtain first structure of non-subtype B HIV-1 protease

  14. Acknowledgments • Ben M. Dunn, Ph.D., College of Medicine, University of Florida • Roxana M. Coman, M.D., Dunn Lab • Melissa Marzahn, Dunn Lab • Marty Fernandez, Dunn Lab • Karan Desai, Dunn Lab • Alex Wlodawer, Ph.D., MCL, NCI-Frederick, NIH • Tinoush Moulaei, Ph.D., Wlodawer Lab • Arnold and Mabel Beckman Foundation

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