In Vivo Selection of HIV-1 Variants with Reduced Susceptibility to the Protease Inhibitor L-735,524 and Related Compounds

  • Emilio A. Emini
  • William A. Schleif
  • Paul Deutsch
  • Jon H. Condra
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 394)


The human immunodeficiency virus type 1 (HIV-1) is a lentivirus that establishes a persistent, long-term infection in its human host. Like all members of this retroviral subfamily, it completes its replication cycle predominantly by budding from the plasma membrane of the infected cell. The newly formed viral particle contains a core that is composed of two copies of the viral genomic RNA and multiple copies of two precursor polyproteins. During or immediately after budding, the polyproteins are cut into subunmits by a virus-specified protease to yield the mature viral core proteins, which include the matrix, capsid and nucleocapsid proteins as well as the viral protease, reverse transcriptase and integrase enzymes. A mature core is essential for viral infectivity. Elimination of virus protease activity through directed mutation of the protease gene results in production of noninfectious mutant viral particles with immature, unprocessed cores.1 Accordingly, the protease is a suitable target for the development of antiviral agents designed to prevent ongoing cycles of the persistent infection.


Protease Gene Human Immunodeficiency Virus Protease Amino Acid Alteration Inhibit Virus Replication Hydroxy Amino 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Kohl NE, Emini EA, Schleif WA et al. Active human immunodeficiency virus protease is required for viral infectivity. Proc Natl Acad Sci USA, 1988; 85: 4686–4690.PubMedCrossRefGoogle Scholar
  2. 2.
    Toh H, Ono M, Saigo K et al. Retroviral protease-like sequence in the yeast transposon Tyl. Nature, 1985; 315: 691–692.CrossRefGoogle Scholar
  3. 3.
    Pearl LH and Taylor WR A structural model for the retroviral proteases. Nature, 1987; 329: 351–354.PubMedCrossRefGoogle Scholar
  4. 4.
    Darke PL, Nutt RF, Brady SF et al. HIV-1 protease specificity of peptide cleavage is sufficient for processing of gag and pol polyproteins. Biochem. Biophys. Res. Commun., 1988; 156: 297–303.PubMedCrossRefGoogle Scholar
  5. 5.
    Kotler M, Katz RA, Danho W et al. Synthetic peptides as substrates and inhibitors of a retroviral protease. Proc Natl Acad Sci USA, 1988; 85: 4185–4189.PubMedCrossRefGoogle Scholar
  6. 6.
    Lillehoj EP, Salazar FHR, Mervis RI et al. Purification and structural characterization of the putative gag-pol protease of human immunodeficiency virus. J Virol, 1988; 62: 3053–3058.PubMedGoogle Scholar
  7. 7.
    Huff JR HIV protease: A novel chemotherapeutic target for AIDS. J Med Chem, 1991; 34: 2305–2314.PubMedCrossRefGoogle Scholar
  8. 8.
    Vacca JP, Dorsey BD, Schleif WA et al. L-735,524, an orally bioavailable HIV-1 protease inhibitor. Proc Natl Acad.Sci USA., 1994; 91: 4096–4100.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1996

Authors and Affiliations

  • Emilio A. Emini
  • William A. Schleif
  • Paul Deutsch
  • Jon H. Condra

There are no affiliations available

Personalised recommendations