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Journal of Virology, May 2000, p. 4621-4633, Vol. 74, No. 10
0022-538X/00/$04.00+0

Identification of a Key Target Sequence To Block Human Immunodeficiency Virus Type 1 Replication within the gag-pol Transframe Domain

Shizuko Sei,1,* Quan-en Yang,1 Dennis O'Neill,1 Kazuhisa Yoshimura,2,dagger Kunio Nagashima,3 and Hiroaki Mitsuya1,2,4

HIV Clinical Interface Laboratory1 and Laboratory of Cell and Molecular Structure,3 SAIC-Frederick, NCI-Frederick Cancer Research and Development Center, Frederick, Maryland 21702; Experimental Retrovirology Section, National Cancer Institute, Bethesda, Maryland 208922; and Department of Internal Medicine II, Kumamoto University School of Medicine, Kumamoto, Japan4

Received 10 November 1999/Accepted 17 February 2000

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 yet 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 p6Gag protein in two different reading frames, can be successfully targeted by an antisense peptide nucleic acid oligomer named PNAPR2. A disrupted translation of gag-pol mRNA induced at the PNAPR2-annealing site resulted in a decreased synthesis of Pr160Gag-Pol polyprotein, hence the viral protease, a predominant expression of Pr55Gag devoid of a fully functional p6Gag protein, and the excessive intracellular cleavage of Gag precursor proteins, hindering the processes of virion assembly. Treatment with PNAPR2 abolished virion production by up to 99% in chronically HIV-1-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.

* Corresponding author. Mailing address: HIV Clinical Interface Laboratory, SAIC Frederick, NCI-Frederick Cancer Research and Development Center, Bldg. 322, Rm. 27B, P.O. Box B, Frederick, MD 21702. Phone: (301) 846-1780. Fax: (301) 846-6067. E-mail: SEI{at}dtpax2.ncifcrf.gov.

dagger Present address: Division of Clinical Retrovirology and Infectious Diseases, Center for AIDS Research, Kumamoto University, Kumamoto, Japan.

Journal of Virology, May 2000, p. 4621-4633, Vol. 74, No. 10
0022-538X/00/$04.00+0


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