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Naturally occurring amino acid polymorphisms in human immunodeficiency virus type 1 (HIV-1) Gag p7(NC) and the C-cleavage site impact Gag-Pol processing by HIV-1 protease.

Publication ,  Journal Article
Goodenow, MM; Bloom, G; Rose, SL; Pomeroy, SM; O'Brien, PO; Perez, EE; Sleasman, JW; Dunn, BM
Published in: Virology
January 5, 2002

Human immunodeficiency virus type 1 (HIV-1) protease activity is targeted at nine cleavage sites comprising different amino acid sequences in the viral Gag-Pol polyprotein. Amino acid polymorphisms in protease and in regions of Gag, particularly p7(NC) and the C-cleavage site between p2 and p7(NC), occur in natural variants of HIV-1 within infected patients. Studies were designed to examine the role of natural polymorphisms in protease and to identify determinants in Gag that modulate protease processing activity. Closely related Gag-Pol regions from an HIV-1-infected mother and two children were evaluated for processing in an inducible expression system, for protease activity on cleavage-site analogues, and for impact on replication by recombinant viruses. Gag-Pol regions displayed one of three processing phenotypes based on the appearance of Gag intermediates and accumulation of mature p24(CA). Gag-Pol regions that were processed rapidly to produce p24(CA) resulted in high-level replication by recombinant viruses, while slow-processing Gag-Pol variants resulted in recombinant viruses that replicated with reduced kinetics in both T cell lines and peripheral blood mononuclear cells. Direct impact by Gag sequences on processing by protease was assessed by construction of chimeric Gag-Pol regions and by site-directed mutagenesis. Optimal protease activity occurred when Gag and Pol regions were derived from the same gag-pol allele. Heterologous Gag regions generally diminished rates and extent of protease processing. Natural polymorphisms in novel positions in p7(NC) and the C-cleavage site have a dominant effect on protease processing activity. Accumulation of Gag products after processing at the C site appears to delay subsequent cleavage and production of mature p24(CA).

Duke Scholars

Published In

Virology

DOI

ISSN

0042-6822

Publication Date

January 5, 2002

Volume

292

Issue

1

Start / End Page

137 / 149

Location

United States

Related Subject Headings

  • gag Gene Products, Human Immunodeficiency Virus
  • Virus Replication
  • Virology
  • Viral Proteins
  • Polymorphism, Genetic
  • Phenotype
  • Molecular Sequence Data
  • Jurkat Cells
  • Humans
  • HIV-1
 

Citation

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Goodenow, M. M., Bloom, G., Rose, S. L., Pomeroy, S. M., O’Brien, P. O., Perez, E. E., … Dunn, B. M. (2002). Naturally occurring amino acid polymorphisms in human immunodeficiency virus type 1 (HIV-1) Gag p7(NC) and the C-cleavage site impact Gag-Pol processing by HIV-1 protease. Virology, 292(1), 137–149. https://doi.org/10.1006/viro.2001.1184
Goodenow, Maureen M., Gregory Bloom, Stephanie L. Rose, Steven M. Pomeroy, Patricia O. O’Brien, Elena E. Perez, John W. Sleasman, and Ben M. Dunn. “Naturally occurring amino acid polymorphisms in human immunodeficiency virus type 1 (HIV-1) Gag p7(NC) and the C-cleavage site impact Gag-Pol processing by HIV-1 protease.Virology 292, no. 1 (January 5, 2002): 137–49. https://doi.org/10.1006/viro.2001.1184.
Goodenow, Maureen M., et al. “Naturally occurring amino acid polymorphisms in human immunodeficiency virus type 1 (HIV-1) Gag p7(NC) and the C-cleavage site impact Gag-Pol processing by HIV-1 protease.Virology, vol. 292, no. 1, Jan. 2002, pp. 137–49. Pubmed, doi:10.1006/viro.2001.1184.
Goodenow MM, Bloom G, Rose SL, Pomeroy SM, O’Brien PO, Perez EE, Sleasman JW, Dunn BM. Naturally occurring amino acid polymorphisms in human immunodeficiency virus type 1 (HIV-1) Gag p7(NC) and the C-cleavage site impact Gag-Pol processing by HIV-1 protease. Virology. 2002 Jan 5;292(1):137–149.
Journal cover image

Published In

Virology

DOI

ISSN

0042-6822

Publication Date

January 5, 2002

Volume

292

Issue

1

Start / End Page

137 / 149

Location

United States

Related Subject Headings

  • gag Gene Products, Human Immunodeficiency Virus
  • Virus Replication
  • Virology
  • Viral Proteins
  • Polymorphism, Genetic
  • Phenotype
  • Molecular Sequence Data
  • Jurkat Cells
  • Humans
  • HIV-1