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Potent inhibition of HIV type 1 infection of mononuclear phagocytes by synthetic peptide analogs of HIV type 1 protease substrates.

Publication ,  Journal Article
Dukes, CS; Matthews, TJ; Lambert, DM; Dreyer, GB; Petteway, SR; Weinberg, JB
Published in: AIDS Res Hum Retroviruses
June 10, 1996

The HIV-1 genome encodes a protease that is required for viral processing of the precursor polyproteins Pr55gag and Pr160gag-pol. Interference with this process in human lymphocytes inhibits production of infectious virus. We tested the ability of several protease inhibitors to decrease replication of HIV-1BaL in human monocytes and peritoneal macrophages. The compounds tested are oligopeptide analogs of HIV-1 protease substrates in which the scissile dipeptide has been replaced by a hydroxyethylene isostere. The protease inhibitors were added only once, 1 hr prior to inoculation with virus. Every 3-5 days, half the medium was replaced with fresh medium. Inhibition of virus production was assessed by measuring reverse transcriptase (RT) activity in supernatant medium 14 days after infection. The concentration of drug required to inhibit infection by 50% (IC50) in monocytes ranged from 0.17 to 2.99 microM; IC50 values for peritoneal macrophages ranged from 0.21 to 1.9 microM. The IC50 values for these compounds were 1.1- to 10-fold higher when tested in monocytes compared to their inhibitory effect in lymphocytes, although still potently effective in the dosage range that appeared nontoxic to cells. Cell toxicity was seen only at concentrations greater than 10 microM, and varied among the drugs tested. Immunoblot analysis of two of the drugs (SB205700 and SB108922) confirmed inhibition of polyprotein processing. In control cells, 22% of viral protein pr55 was processed to p24 by 24 hr, and 51% was processed by 48 hr. In cells treated with the protease inhibitors (2 microM), Pr55 processing was inhibited 77% at 24 hr and 89% at 48 hr. Thus, these synthetic peptide analogs potently inhibit productive infection of mononuclear phagocytes by HIV-1. Drugs of this class may be useful for the treatment of HIV-1 infection in humans.

Duke Scholars

Published In

AIDS Res Hum Retroviruses

DOI

ISSN

0889-2229

Publication Date

June 10, 1996

Volume

12

Issue

9

Start / End Page

777 / 782

Location

United States

Related Subject Headings

  • Virology
  • Tumor Cells, Cultured
  • Structure-Activity Relationship
  • Oligopeptides
  • Monocytes
  • Molecular Structure
  • Macrophages, Peritoneal
  • Humans
  • HIV-1
  • HIV Protease Inhibitors
 

Citation

APA
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MLA
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Dukes, C. S., Matthews, T. J., Lambert, D. M., Dreyer, G. B., Petteway, S. R., & Weinberg, J. B. (1996). Potent inhibition of HIV type 1 infection of mononuclear phagocytes by synthetic peptide analogs of HIV type 1 protease substrates. AIDS Res Hum Retroviruses, 12(9), 777–782. https://doi.org/10.1089/aid.1996.12.777
Dukes, C. S., T. J. Matthews, D. M. Lambert, G. B. Dreyer, S. R. Petteway, and J. B. Weinberg. “Potent inhibition of HIV type 1 infection of mononuclear phagocytes by synthetic peptide analogs of HIV type 1 protease substrates.AIDS Res Hum Retroviruses 12, no. 9 (June 10, 1996): 777–82. https://doi.org/10.1089/aid.1996.12.777.
Dukes CS, Matthews TJ, Lambert DM, Dreyer GB, Petteway SR, Weinberg JB. Potent inhibition of HIV type 1 infection of mononuclear phagocytes by synthetic peptide analogs of HIV type 1 protease substrates. AIDS Res Hum Retroviruses. 1996 Jun 10;12(9):777–82.
Dukes, C. S., et al. “Potent inhibition of HIV type 1 infection of mononuclear phagocytes by synthetic peptide analogs of HIV type 1 protease substrates.AIDS Res Hum Retroviruses, vol. 12, no. 9, June 1996, pp. 777–82. Pubmed, doi:10.1089/aid.1996.12.777.
Dukes CS, Matthews TJ, Lambert DM, Dreyer GB, Petteway SR, Weinberg JB. Potent inhibition of HIV type 1 infection of mononuclear phagocytes by synthetic peptide analogs of HIV type 1 protease substrates. AIDS Res Hum Retroviruses. 1996 Jun 10;12(9):777–782.
Journal cover image

Published In

AIDS Res Hum Retroviruses

DOI

ISSN

0889-2229

Publication Date

June 10, 1996

Volume

12

Issue

9

Start / End Page

777 / 782

Location

United States

Related Subject Headings

  • Virology
  • Tumor Cells, Cultured
  • Structure-Activity Relationship
  • Oligopeptides
  • Monocytes
  • Molecular Structure
  • Macrophages, Peritoneal
  • Humans
  • HIV-1
  • HIV Protease Inhibitors