Abstract
The protease encoded in the HIV-1 genome plays a crucial role in the life cycle of the virus, cleaving the p55gag and p160gag-pol precursors into their mature and functional forms Since either genetic inactivation or chemical inhibition of the protease results in the production of non-infectious viral particles, the development of inhibitors of the HIV-1 protease has been pursued as a means of preventing viral replication. Although many inhibitors now exist that can block viral maturation and slow viral replication in vivo, resistance to the inhibitors over a prolonged period of time is often observed [2–5]. We are interested in defining the role of the protease in the viral life cycle by engineering variant forms of the enzyme with known properties. This approach has led us to consider an alternate method of regulating the activity of HIV protease for potential therapeutic intervention.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Kohl NE, Emini EA, Schleif WA, Davis LJ, Heimbach JC, Dixon RA, Scolnick EM and Sigal IS, Active human immunodeficiency virus protease is required for viral infectivity. Proc Natl Acad Sei U S A 85(13): 4686–90, 1988.
Martin LN, Soike KF, Murphey-Corb M, Bohm RP, Roberts ED, Kakuk TJ, Thaisrivongs S, Vidmar TJ, Ruwart MJ, Davio SR and et al., Effects of U-75875, a peptidomimetic inhibitor of retroviral proteases, on simian immunodeficiency virus infection in rhesus monkeys. Antimicrob Agents Chemother 38(6): 1277–83, 1994.
McQuade TJ, Tomasselli AG, Liu L, Karacostas V, Moss B, Sawyer TK, Heinrikson RL and Tarpley WG, A synthetic HIV-1 protease inhibitor with antiviral activity arrests HIV-like particle maturation. Science 247(4941): 454–6, 1990.
Tomasselli AG, Howe WJ, Sawyer TK, Wlodawer A and Heinrikson RL, The complexities of AIDS: an assessment of the HIV protease as a therapeutic target. Chim. Oggi: 6–274, 1991.
Wlodawer A and Erickson JW, Structure-based inhibitors of HIV-1 protease. Annu Rev Biochem 62: 543–85, 1993.
Pearl LH and Taylor WR, A structural model for the retroviral proteases. Nature 329(6137): 351–4, 1987.
Wlodawer A, Miller M, Jaskolski M, Sathyanarayana BK, Baldwin E, Weber IT, Selk LM, Clawson L, Schneider J and Kent SB, Conserved folding in retroviral proteases: crystal structure of a synthetic HIV-1 protease. Science 245(4918): 616–21, 1989.
Navia MA, Fitzgerald PM, McKeever BM, Leu CT, Heimbach JC, Herber WK, Sigal IS, Darke PL and Springer JP, Three-dimensional structure of aspartyl protease from human immunodeficiency virus HIV-1. Nature 337(6208): 615–20, 1989.
Babé LM, Rosé J and Craik CS, Synthetic “interface” peptides alter dimeric assembly of the HIV 1 and 2 proteases. Protein Science 1(10): 1244–53, 1992.
Cheng YS, Yin FH, Foundling S, Blomstrom D and Kettner CA, Stability and activity of human immunodeficiency virus protease: comparison of the natural dimer with a homologous, single-chain tethered dimer. Proc Natl Acad Sei U S A 87(24): 9660–4, 1990.
Zhang ZY, Poorman RA, Maggiora LL, Heinrikson RL and Kezdy FJ, Dissociative inhibition of dimeric enzymes. Kinetic characterization of the inhibition of HIV-1 protease by its COOH-terminal tetrapeptide. J Biol Chem 266(24): 15591–4, 1991.
Krausslich HG, Human immunodeficiency virus proteinase dimer as component of the viral polyprotein prevents particle assembly and viral infectivity. Proc Natl Acad Sei U S A 88(8): 3213–7, 1991.
Stephens EB and Compans RW, Assembly of animal viruses at cellular membranes. Annu Rev Microbiol 42:489–516, 1988.
Debouck C, Gorniak JG, Strickler JE, Meek TD, Metcalf BW and Rosenberg M, Human immunodeficiency virus protease expressed in Escherichia coli exhibits autoprocessing and specific maturation of the gag precursor. Proc Natl Acad Sei U S A 84(24): 8903–6, 1987.
Gottlinger HG, Sodroski JG and Haseltine WA, Role of capsid precursor processing and myristoylation in morphogenesis and infectivity of human immunodeficiency virus type 1. Proc Natl Acad Sei U S A 86(15): 5781–5, 1989.
Peng C, Ho BK, Chang TW and Chang NT, Role of human immunodeficiency virus type 1-specific protease in core protein maturation and viral infectivity. J Virol 63(6): 2550–6, 1989.
Kaplan AH, Zack JA, Knigge M, Paul DA, Kempf DJ, Norbeck DW and Swanstrom R, Partial inhibition of the human immunodeficiency virus type 1 protease results in aberrant virus assembly and the formation of noninfectious particles. J Virol 67(7): 4050–5, 1993.
Rosé JR, Babe LM and Craik CS, Defining the level of human immunodeficiency virus type 1 (HIV-1) protease activity required for HIV-1 particle maturation and infectivity. J Virol 69(5): 2751–8, 1995.
Page KA, Landau NR and Littman DR, Construction and use of a human immunodeficiency virus vector for analysis of virus infectivity. J Virol 64(11): 5270–6, 1990.
Herskowitz I, Functional inactivation of genes by dominant negative mutations. Nature 329(6136): 219–22, 1987.
Feinberg MB and Trono D, Intracellular immunization: trans-dominant mutants of HIV gene products as tools for the study and interruption of viral replication. AIDS Res Hum Retroviruses 8(6): 1013–22, 1992.
Trono D, Feinberg MB and Baltimore D, HIV-1 Gag mutants can dominantly interfere with the replication of the wild-type virus. Cell 59(1): 113–20, 1989.
Malim MH, Bohnlein S, Hauber J and Cullen BR, Functional dissection of the HIV-1 Rev trans-activator-derivation of a trans-dominant repressor of Rev function. Cell 58(1): 205–14, 1989.
Hope TJ, Klein NP, Elder ME and Parslow TG, trans-dominant inhibition of human immunodeficiency virus type 1 Rev occurs through formation of inactive protein complexes. J Virol 66(4): 1849–55, 1992.
Bahner I, Zhou C, Yu XJ, Hao QL, Guatelli JC and Kohn DB, Comparison of trans-dominant inhibitory mutant human immunodeficiency virus type 1 genes expressed by retroviral vectors in human T lymphocytes. J Virol 67(6): 3199–207, 1993.
Smythe JA, Sun D, Thomson M, Markham PD, Reitz MS, Jr., Gallo RC and Lisziewicz J, A Rev-inducible mutant gag gene stably transferred into T lymphocytes: an approach to gene therapy against human immunodeficiency virus type 1 infection. Proc Natl Acad Sei U S A 91(9): 3657–61, 1994.
Babé LM, Pichuantes S and Craik CS, Inhibition of HIV protease activity by heterodimer formation. Biochemistry 30(1): 106–11, 1991.
Babé LM, Rosé J and Craik CS, Trans-dominant inhibitory human immunodeficiency virus type 1 protease monomers prevent protease activation and virion maturation. Proc Natl Acad Sei U S A 92(22): 10069–73, 1995.
Condra JH, Schleif WA, Blahy OM, Gabryelski LJ, Graham DJ, Quintero JC, Rhodes A, Robbins HL, Roth E, Shivaprakash M and et al., In vivo emergence of HIV-1 variants resistant to multiple protease inhibitors. Nature 374(6522): 569–71, 1995.
Dauber D, McPhee F, Ünal A and Craik CS, Optimization of a macromolecular inhibitor of HIV-1 protease. In: Structure and Function of Aspartic Proteinases: Retroviral and Cellular Enzymes (Ed, James MNG). Plenum Publishing Corporation, New York, 1997.
McPhee F, Good AC, Kuntz ID and Craik CS, Engineering HIV-1 protease heterodimers as macromolecular inhibitors of viral maturation. Proc. Natl. Acad. Sci. 93: 11477–81, 1996.
Escaich S, Kalfoglou C, Plavec I, Kaushal S, Mosca JD and Bohnlein E, RevM10-mediated inhibition of HIV-1 replication in chronically infected T cells. Hum Gene Ther 6(5): 625–34, 1995.
Junker U, Escaich S, Plavec I, Baker J, McPhee F, Rosé JR, Craik CS and Böhnlein E, Intracellular expression of HIV-1 protease variants inhibits replication of wild-type and protease inhibitor resistant HIV-1 strains in human T cell lines. J. Virology 70: 7765–72, 1996.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1998 Springer Science+Business Media New York
About this chapter
Cite this chapter
Craik, C.S., Babé, L.M., Dauber, D., McPhee, F., Rosé, J., Ünal, A. (1998). Engineering Catalytically Defective Forms of HIV Protease to Modulate Its Activity. In: James, M.N.G. (eds) Aspartic Proteinases. Advances in Experimental Medicine and Biology, vol 436. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-5373-1_4
Download citation
DOI: https://doi.org/10.1007/978-1-4615-5373-1_4
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4613-7452-7
Online ISBN: 978-1-4615-5373-1
eBook Packages: Springer Book Archive