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Journal of Virology, October 2004, p. 10747-10754, Vol. 78, No. 19
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.19.10747-10754.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Entry and Transcription as Key Determinants of Differences in CD4 T-Cell Permissiveness to Human Immunodeficiency Virus Type 1 Infection{dagger}

Angela Ciuffi,1 Gabriela Bleiber,1 Miguel Muñoz,1 Raquel Martinez,1 Corinne Loeuillet,1 Manuela Rehr,2 Marek Fischer,3 Huldrych F. Günthard,3 Annette Oxenius,2 Pascal Meylan,1 Sebastian Bonhoeffer,4 Didier Trono,5 and Amalio Telenti1*

Institute of Microbiology, University of Lausanne, Lausanne,1 Institute for Microbiology,2 Ecology and Evolution, ETH Zurich,4 Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich,3 Department of Genetics and Microbiology, University of Geneva, Geneva, Switzerland5

Received 25 March 2004/ Accepted 13 June 2004

Isolated primary human cells from different donors vary in their permissiveness—the ability of cells to be infected and sustain the replication of human immunodeficiency virus type 1 (HIV-1). We used replicating HIV-1 and single-cycle lentivirus vectors in a population approach to identify polymorphic steps during viral replication. We found that phytohemagglutinin-stimulated CD4+ CD45RO+ CD57– T cells from healthy blood donors (n = 128) exhibited a 5.2-log-unit range in virus production. For 20 selected donors representing the spectrum of CD4 T-cell permissiveness, we could attribute up to 42% of the total variance in virus production to entry factors and 48% to postentry steps. Efficacy at key intracellular steps of the replicative cycle (reverse transcription, integration, transcription and splicing, translation, and budding and release) varied from 0.71 to 1.45 log units among donors. However, interindividual differences in transcription efficiency alone accounted for 64 to 83% of the total variance in virus production that was attributable to postentry factors. While vesicular stomatitis virus G protein-mediated fusion was more efficacious than CCR5/CD4 entry, the latter resulted in greater transcriptional activity per proviral copy. The phenotype of provirus transcription was stable over time, indicating that it represents a genetic trait.

* Corresponding author. Mailing address: Institute of Microbiology, 1011 Lausanne, Switzerland. Phone: 41 21 314 0550. Fax: 41 21 314 4095. E-mail: amalio.telenti{at}hospvd.ch.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

Journal of Virology, October 2004, p. 10747-10754, Vol. 78, No. 19
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.19.10747-10754.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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