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Journal of Virology, February 2004, p. 2082-2087, Vol. 78, No. 4
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.4.2082-2087.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

The Human Immunodeficiency Virus Type 1 Ribosomal Frameshifting Site Is an Invariant Sequence Determinant and an Important Target for Antiviral Therapy

Preetha Biswas,1 Xi Jiang,1 Annmarie L. Pacchia,1 Joseph P. Dougherty,1 and Stuart W. Peltz1,2*

Department of Molecular Genetics, Microbiology and Immunology, Robert Wood Johnson Medical School-University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey 08854,1 PTC Therapeutics, South Plainfield, New Jersey 070802

Received 14 April 2003/ Accepted 24 October 2003

Human immunodeficiency virus type 1 (HIV-1) utilizes a distinctive form of gene regulation as part of its life cycle, termed programmed -1 ribosomal frameshifting, to produce the required ratio of the Gag and Gag-Pol polyproteins. We carried out a sequence comparison of 1,000 HIV-1 sequences at the slippery site (UUUUUUA) and found that the site is invariant, which is somewhat surprising for a virus known for its variability. This prompted us to prepare a series of mutations to examine their effect upon frameshifting and viral infectivity. Among the series of mutations were changes of the HIV-1 slippery site to those effectively utilized by other viruses, because such mutations would be anticipated to have a relatively mild effect upon frameshifting. The results demonstrate that any change to the slippery site reduced frameshifting levels and also dramatically inhibited infectivity. Because ribosomal frameshifting is essential for HIV-1 replication and it is surprisingly resistant to mutation, modulation of HIV-1 frameshifting efficiency potentially represents an important target for the development of novel antiviral therapeutics.

* Corresponding author. Mailing address: Department of Molecular Genetics, Microbiology and Immunology, Robert Wood Johnson Medical School-UMDNJ, 675 Hoes Lane, Piscataway, NJ 08854. Phone: (908) 222-7000. Fax: (908) 222-7321. E-mail: peltz{at}umdnj.edu.

Journal of Virology, February 2004, p. 2082-2087, Vol. 78, No. 4
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.4.2082-2087.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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