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Natural variation in HIV-1 protease, Gag p7 and p6, and protease cleavage sites within gag/pol polyproteins: amino acid substitutions in the absence of protease inhibitors in mothers and children infected by human immunodeficiency virus type 1.

Publication ,  Journal Article
Barrie, KA; Perez, EE; Lamers, SL; Farmerie, WG; Dunn, BM; Sleasman, JW; Goodenow, MM
Published in: Virology
May 15, 1996

Reduced sensitivity of human immunodeficiency virus type 1 (HIV-1) to protease inhibitors is associated with multiple amino acid substitutions in the virus-encoded protease. The combination of changes that contribute to drug resistance is dependent in part upon the amino acid residues comprising protease alleles prior to drug therapy. We analyzed within peripheral blood mononuclear cells from HIV-1-infected mothers and their children viral gag/pol regions, which included p7, transframe p6/p6*, and protease coding sequences, as well as six protease cleavage sites. Sixty protease alleles from 12 individuals differed by at least 3 to as many as 10 amino acids from proteases encoded by molecular clones of HIV-1, indicating that there is no prototype or consensus wild-type HIV-1 protease sequence. Protease variants with a proline at position 63, a substitution associated with resistance to protease inhibitors, appeared in the absence of antiprotease therapy in 7 patients and were transmitted by 2 mothers to their infants. Gag p7 p6 regions were significantly more variable than protease. The p6/p6* region contained length variants and amino acid repeats in both reading frames. Five protease cleavage sites (B, D', D, E, and F) contained highly conserved amino acid sequences in individuals infected by epidemiologically distinct viruses. In contrast, C cleavage sites, localized between Gag p2 and Gag p7, displayed considerable amino acid variability, were unique among groups of infected individuals, and appeared to be related to particular protease alleles. Genetic variability in vivo in protease, in cleavage sites, and in proteins upstream of protease provides the potential to modulate enzyme activity and susceptibility to protease inhibitors.

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Published In

Virology

DOI

ISSN

0042-6822

Publication Date

May 15, 1996

Volume

219

Issue

2

Start / End Page

407 / 416

Location

United States

Related Subject Headings

  • pol Gene Products, Human Immunodeficiency Virus
  • gag Gene Products, Human Immunodeficiency Virus
  • Virology
  • Viral Proteins
  • Protein Precursors
  • Phylogeny
  • Molecular Sequence Data
  • Humans
  • HIV-1
  • HIV Protease Inhibitors
 

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Barrie, K. A., Perez, E. E., Lamers, S. L., Farmerie, W. G., Dunn, B. M., Sleasman, J. W., & Goodenow, M. M. (1996). Natural variation in HIV-1 protease, Gag p7 and p6, and protease cleavage sites within gag/pol polyproteins: amino acid substitutions in the absence of protease inhibitors in mothers and children infected by human immunodeficiency virus type 1. Virology, 219(2), 407–416. https://doi.org/10.1006/viro.1996.0266
Barrie, K. A., E. E. Perez, S. L. Lamers, W. G. Farmerie, B. M. Dunn, J. W. Sleasman, and M. M. Goodenow. “Natural variation in HIV-1 protease, Gag p7 and p6, and protease cleavage sites within gag/pol polyproteins: amino acid substitutions in the absence of protease inhibitors in mothers and children infected by human immunodeficiency virus type 1.Virology 219, no. 2 (May 15, 1996): 407–16. https://doi.org/10.1006/viro.1996.0266.
Journal cover image

Published In

Virology

DOI

ISSN

0042-6822

Publication Date

May 15, 1996

Volume

219

Issue

2

Start / End Page

407 / 416

Location

United States

Related Subject Headings

  • pol Gene Products, Human Immunodeficiency Virus
  • gag Gene Products, Human Immunodeficiency Virus
  • Virology
  • Viral Proteins
  • Protein Precursors
  • Phylogeny
  • Molecular Sequence Data
  • Humans
  • HIV-1
  • HIV Protease Inhibitors