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Journal of Virology, December 2004, p. 13072-13081, Vol. 78, No. 23
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.23.13072-13081.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Lentiviral Vectors Interfering with Virus-Induced CD4 Down-Modulation Potently Block Human Immunodeficiency Virus Type 1 Replication in Primary Lymphocytes

Hang M. Pham,1 Enrique R. Argañaraz,1 Bettina Groschel,1 Didier Trono,2 and Juan Lama1,3*

Department of Medicine,1 Rebecca and John Moores UCSD Cancer Center, University of California at San Diego, School of Medicine, La Jolla, California,3 Department of Genetics and Microbiology, CMU, Faculty of Medicine, University of Geneva, Switzerland2

Received 7 May 2004/ Accepted 28 July 2004

CD4 down-modulation is essential for the production of human immunodeficiency virus (HIV) infectious particles. Disease progression correlates with enhanced viral induced CD4 down-modulation, and a subset of long-term nonprogressors carry viruses defective in this function. Despite multiple pieces of evidence highlighting the importance of this function in viral pathogenesis in vivo, to date, HIV-induced CD4 down-modulation has not been used as a target for intervention. We describe here HIV-based vectors that deliver truncated CD4 molecules resistant to down-modulation by the viral products Nef and Vpu. Infection of cells previously transduced with these vectors proceeded normally, and viral particles were released in normal amounts. However, the infectivity of the released virions was reduced 1,000-fold. Lentiviral vectors expressing truncated CD4 molecules were efficient at blocking HIV-1 infectivity and replication in several cell lines and in CD4-positive primary lymphocytes. The findings presented here provide proof-of-principle that approaches targeting the virus-induced CD4 down-modulation may constitute the basis for novel anti-HIV therapies.

* Corresponding author. Present address: La Jolla Institute for Molecular Medicine, 4570 Executive Dr., Suite 100, San Diego, CA 92121. Phone: (858) 232-7919. Fax: (858) 587-6742. E-mail: jlama{at}ljimm.org.

Journal of Virology, December 2004, p. 13072-13081, Vol. 78, No. 23
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.23.13072-13081.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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