Role of HIV Gag mutations in acquisition of resistance to protease inhibitors.

• Project/Area Number: 21790527
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Applied pharmacology
• Research Institution: Kumamoto Health Science University
• Principal Investigator: 青木 学 Kumamoto Health Science University, 保健科学部, 講師 (70389542)
• Project Period (FY): 2009 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2010: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2009: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: HIV / 薬剤耐性 / プロテアーゼ阻害剤

Research Abstract

We have identified six amino acid substitutions in the Gag region in in vitro selected amprenavir (APV)-resistant viruses. An infectious recombinant HIV-1 clone carrying the Gag mutations developed APV resistance more quickly than wild-type HIV-1, however it delayed the acquisition of resistance against nelfinavir (NFV) which is another PI, suggesting that antiretroviral regimens including both APV and NFV may bring about favorable antiviral efficacy. The present data suggests that the preexistence of certain Gag mutations related to PI resistance can accelerate the emergence of resistance to the PI and delay the acquisition of HIV resistance to other PIs. These findings should have clinical relevance in the therapy of HIV-1 infection with PI-including regimens.

Research Products

• [Journal Article] Novel HIV-1 protease inhibitors (PIs)containing a bicyclic P2 functional moiety, tetrahydropyrano-tetrahydrofuran, that are potent against multi-PI-resistant HIV-1 variants. (2011)
  • Author(s): Ide K, Aoki M, Amano M, Koh Y, Yedidi RS, Das D, Leschenko S, Chapsal B, Ghosh AK, Mitsuya H.
  • Journal Title: Antimicrob. Agents Chemother. 55 Pages: 1717-1727
  • Peer Reviewed
• [Journal Article] Probing Multidrug-Resistance and Protein-Ligand Interactions with Oxatricyclic Designed Ligands in HIV-1 Protease Inhibitors. (2010)
  • Author(s): Ghosh AK, Xu CX, Rao KV, Baldridge A, Agniswamy J, Wang YF, Weber IT, Aoki M, Miguel SG, Amano M, Mitsuya H.
  • Journal Title: ChemMedChem. 8 Pages: 1850-1854
  • Peer Reviewed
• [Journal Article] Novel Protease Inhibitors(PIs)Containing Macrocyclic Components and 3(R),3a(S),6a(R)-bis-Tetrahydrofuranylurethane(bis-THF) That Are Potent Against Multi-PI-Resistant HIV-1 Variants In Vitro. (2010)
  • Author(s): Tojo Y, Koh Y, Amano M, Aoki M, Das D, Ghosh AK, Mitsuya H.
  • Journal Title: Antimicrob. Agents Chemother. 54 Pages: 3460-3470
  • Peer Reviewed
• [Journal Article] Probing multidrug-resistance and protein-ligand interactions with oxatricyclic designed ligands in HIV-1 protease inhibitors. (2010)
  • Author(s): Ghosh AK, Xu CX, Rao KV, Baldridge A, Agniswamy J, Wang YF, Weber IT, Aoki M, Miguel SG, Amano M, Mitsuya H.
  • Journal Title: ChemMedChem Volume: Vol.8 Pages: 1850-1854
  • Peer Reviewed
• [Journal Article] Novel protease inhibitors (PIs) containing macrocyclic components and 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane that are potent against multi-PI-resistant HIV-1 variants in vitro. (2010)
  • Author(s): Tojo Y, Koh Y, Amano M, Aoki M, Das D, Kulkarni S, Anderson DD, Ghosh AK, Mitsuya H.
  • Journal Title: Antimicrobial Agents and Chemotherapy Volume: Vol.54 Pages: 3460-3470
  • Peer Reviewed
• [Journal Article] Non-cleavage site Gag mutations in amprenavir-resistant HIV-1 Predispose HIV-1 to rapid acquisition of amprenaive resistance but delays development of resistance to other protease inhibitors. (2009)
  • Author(s): Aoki M, Venzon DJ, Koh Y, Aoki-Ogata H, Miyakawa T, Yoshimura K, Maeda K, Mitsuya H.
  • Journal Title: J.Virol. 83 Pages: 3059-3068
  • Peer Reviewed
• [Journal Article] Non-cleavage site Gag mutations in amprenavir-resistant HIV-1 predispose HIV-1 to rapid acquisition of amprenavir resistance but delays development of resistance to other protease inhibitors (2009)
  • Author(s): Manabu Aoki
  • Journal Title: Journal of Virology Vol.83 Pages: 3059-3068
  • Peer Reviewed
• [Presentation] Tipranaivr (TPV)-resistant HIV-1 lacks both protease enzvmatic inhibition and dimerization inhibition activity. (2011)
  • Author(s): M.Aoki, K.Ide, M.L.Danish, Y.Koh, H.Mitsuya.
  • Organizer: 18th Conference on retroviruses and opportunistic infections
  • Place of Presentation: Hynes convention center (Boston, MA, US)
  • Year and Date: 2011-03-02
• [Presentation] Tipranavir (TPV)-resistant HIV-1 lacks both protease enzymatic inhibition and dimerization inhibition activity. (2011)
  • Author(s): M.Aoki, K.Ide, M.L.Danish, Y.Koh, H.Mitsuya.
  • Organizer: 18th Conference on Retroviruses and Opportunistic Infections.
  • Place of Presentation: Boston, MA, USA.
• [Presentation] Tipranavir 耐性HIV はプロテアーゼ二量体化阻止能と酵素活性阻止能の双方を喪失している (2010)
  • Author(s): 青木学、井手一彦、M.L.Danish、満屋裕明
  • Organizer: 第24回日本エイズ学会学術集会
  • Place of Presentation: 東京都
  • Year and Date: 2010-11-25
• [Presentation] Tipranavir耐性HIVはtipranavirのプロテアーゼ二量体化阻止能と酵素活性阻止能の双方に抵抗する (2010)
  • Author(s): 青木学、井手一彦、M.L.Danish、満屋裕明
  • Organizer: 第24回日本エイズ学会学術集会・総会
  • Place of Presentation: グランドプリンスホテル高輪(東京都)
  • Year and Date: 2010-11-25
• [Presentation] Tipranavir 耐性HIVはプロテアーゼ二量体化阻止能と酵素活性阻止能の双方を喪失している (2010)
  • Author(s): 青木学、井手一彦、M.L.Danish、満屋裕明
  • Organizer: 第20回抗ウイルス療法研究会学術集会
  • Place of Presentation: 熊本県
  • Year and Date: 2010-05-21
• [Presentation] Early phase dynamics of HIV-1 infection in hPBM-transplanted NOD/SCID/Jak3-/-mice using infectious HIV-1 carrying fluorescent protein mCherry. (2010)
  • Author(s): N.Higash-Kuwata, H.Aoki-Ogata, S.Hattori, T.Nakamura, M.Aoki, S.Okada, H.Mitsuya.
  • Organizer: XVIII International AIDS Conference.
  • Place of Presentation: Vienna, Austria.
• [Presentation] Novel HIV-1 protease inhibitors () containing bis-tetrahydrofuran (bis-THF) and a novel polycyclic ligand. (2010)
  • Author(s): K.Ide, M.Aoki, Y.Koh, M.Amano, D.D.Anderson, B.Chapsal, A.K.Ghosh, H.Mitsuya.
  • Organizer: XVIII International AIDS Conference.
  • Place of Presentation: Vienna, Austria.
• [Presentation] The Binary Protease Inhibitor, Darunavir, Has a High Genetic Barrier to the Emergence of Resistant HIV-1 Variants. (2010)
  • Author(s): Yasuhiro Koh, M Aoki, M Amano, H Ogata-Aoki, S Leschenko-Yashchuk, A Ghosh, H Mitsuya.
  • Organizer: 17th Conference on Retroviruses and Opportunistic Infections.
  • Place of Presentation: San Francisco, CA, USA.
• [Presentation] 複数のプロテアーゼ阻害剤耐性臨床分離株を用いて誘導したtipranavir 耐性HIV 変異体の解析 (2009)
  • Author(s): 青木学、こう康博、天野将之、東條靖、満屋裕明
  • Organizer: 第23回日本エイズ学会学術集会
  • Place of Presentation: 愛知県
  • Year and Date: 2009-11-26
• [Presentation] 複数のプロテアーゼ阻害剤耐性臨床HIV分離株を用いて誘導した tipranavir 高度耐性変異株の解析 (2009)
  • Author(s): 青木学
  • Organizer: 第23回日本エイズ学会学術集会・総会
  • Place of Presentation: 名古屋国際会議場(愛知県)
  • Year and Date: 2009-11-26
• [Presentation] The binary mechanism of HIV-1 resistance to tipranaivr(TPV) : Loss of inhibition of pretease catalytic activity and protease dimerization (2009)
  • Author(s): 青木学
  • Organizer: 49th Interscience conference on antimicrobial agents and chemotherapy
  • Place of Presentation: The moscone center(San Francisco, CA, US)
  • Year and Date: 2009-09-13
• [Presentation] The binary mechanism of HIV-1 resistance to tipranavie (TPV) : Loss of inhibition of protease catalytic activity and protease dimerization. (2009)
  • Author(s): M.Aoki, Y.Koh, K.Ide, M.L.Danish, H.Aoki-Ogata, H.Mitsuya.
  • Organizer: 49th Interscience conference on antimicrobial agents and chemotherapy.
  • Place of Presentation: San Francisco, CA, USA.