This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Sei, S.
Right arrow Articles by Mitsuya, H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sei, S.
Right arrow Articles by Mitsuya, H.

 Previous Article  |  Next Article 

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


This article has been cited by other articles:

  • Zhu, W., Burnette, A., Dorjsuren, D., Roberts, P. E., Huleihel, M., Shoemaker, R. H., Marquez, V. E., Agbaria, R., Sei, S. (2005). Potent Antiviral Activity of North-Methanocarbathymidine against Kaposi's Sarcoma-Associated Herpesvirus. Antimicrob. Agents Chemother. 49: 4965-4973 [Abstract] [Full Text]  
  • Yang, Q.-e., Stephen, A. G., Adelsberger, J. W., Roberts, P. E., Zhu, W., Currens, M. J., Feng, Y., Crise, B. J., Gorelick, R. J., Rein, A. R., Fisher, R. J., Shoemaker, R. H., Sei, S. (2005). Discovery of Small-Molecule Human Immunodeficiency Virus Type 1 Entry Inhibitors That Target the gp120-Binding Domain of CD4. J. Virol. 79: 6122-6133 [Abstract] [Full Text]  
  • Folini, M., Berg, K., Millo, E., Villa, R., Prasmickaite, L., Daidone, M. G., Benatti, U., Zaffaroni, N. (2003). Photochemical Internalization of a Peptide Nucleic Acid Targeting the Catalytic Subunit of Human Telomerase. Cancer Res. 63: 3490-3494 [Abstract] [Full Text]  
  • Kawamura, T., Gatanaga, H., Borris, D. L., Connors, M., Mitsuya, H., Blauvelt, A. (2003). Decreased Stimulation of CD4+ T Cell Proliferation and IL-2 Production by Highly Enriched Populations of HIV-Infected Dendritic Cells. J. Immunol. 170: 4260-4266 [Abstract] [Full Text]  
  • Kaushik, N., Basu, A., Palumbo, P., Myers, R. L., Pandey, V. N. (2002). Anti-TAR Polyamide Nucleotide Analog Conjugated with a Membrane-Permeating Peptide Inhibits Human Immunodeficiency Virus Type 1 Production. J. Virol. 76: 3881-3891 [Abstract] [Full Text]  
  • Gatanaga, H., Suzuki, Y., Tsang, H., Yoshimura, K., Kavlick, M. F., Nagashima, K., Gorelick, R. J., Mardy, S., Tang, C., Summers, M. F., Mitsuya, H. (2002). Amino Acid Substitutions in Gag Protein at Non-cleavage Sites Are Indispensable for the Development of a High Multitude of HIV-1 Resistance against Protease Inhibitors. J. Biol. Chem. 277: 5952-5961 [Abstract] [Full Text]  
  • Peters, S., Munoz, M., Yerly, S., Sanchez-Merino, V., Lopez-Galindez, C., Perrin, L., Larder, B., Cmarko, D., Fakan, S., Meylan, P., Telenti, A. (2001). Resistance to Nucleoside Analog Reverse Transcriptase Inhibitors Mediated by Human Immunodeficiency Virus Type 1 p6 Protein. J. Virol. 75: 9644-9653 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»