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Identification of a key target sequence to block human immunodeficiency virus type 1 replication within the gag-pol transframe domain

  1. Author:
    Sei, S.
    Yang, Q. E.
    O'Neill, D.
    Yoshimura, K.
    Nagashima, K.
    Mitsuya, H.

  2. Author Address

    Sei S NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, HIV Clin Interface Lab Bldg 322,Rm 27B,POB B Frederick, MD 21702 USA NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, HIV Clin Interface Lab Frederick, MD 21702 USA NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Lab Cell & Mol Struct Frederick, MD 21702 USA NCI, Expt Retrovirol Sect Bethesda, MD 20892 USA Kumamoto Univ, Sch Med, Dept Internal Med 2 Kumamoto 860 Japan
    1. Year: 2000
  2. Journal: Journal of Virology
    1. 74
    2. 10
    3. Pages: 4621-4633
  4. Type of Article: Review
  1. Abstract:

    Although the full sequence of the human immunodeficiency virus type 1 (HIV-1) genome has been known for more than a decade, effective genetic antivirals have Set to be developed. Here we show that, of 22 regions examined, one highly conserved sequence (ACTCTTTGGCAACGA) near the 3' end of the HIV-1 gag-pol transframe region, encoding viral protease residues 4 to 8 and a C-terminal Vpr-binding motif of p6(Gag) protein in two different reading frames, can be successfully targeted by an antisense peptide nucleic acid oligomer named PNA(PR2). A disrupted translation of gag-pol mRNA induced at the PNA(PR2)-annealing site resulted in a decreased synthesis of pr160(Gag-Pol) polyprotein, hence the viral protease, a predominant expression of pr55(Gag) devoid of a fully functional p6(Gag) protein, and the excessive intracellular cleavage of Gag precursor proteins, hindering the processes of virion assembly. Treatment with PNA(PR2) abolished virion production by up to 99% in chronically HIV-l-infected H9 cells and in peripheral blood mononuclear cells infected with clinical HIV-1 isolates with the multidrug-resistant phenotype. This particular segment of the gag-pol transframe gene appears to offer a distinctive advantage over other regions in invading viral structural genes and restraining HIV-1 replication in infected cells and may potentially be exploited as a novel antiviral genetic target. [References: 154]

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