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Journal of Virology, April 2004, p. 3675-3683, Vol. 78, No. 7
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.7.3675-3683.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Human Immunodeficiency Virus Type 1 Subtypes Have a Distinct Long Terminal Repeat That Determines the Replication Rate in a Host-Cell-Specific Manner

Tim van Opijnen,1,2 Rienk E. Jeeninga,1 Maarten C. Boerlijst,2 Georgios P. Pollakis,1 Veera Zetterberg,3 Mika Salminen,3 and Ben Berkhout1*

Department of Human Retrovirology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam,1 Section Population Biology, Institute for Biodiversity and Ecosystem Dynamics, University of Amsterdam, 1098 SM Amsterdam, The Netherlands,2 HIV Laboratory, Department of Infectious Disease Epidemiology, National Public Health Institute, 00300 Helsinki, Finland3

Received 19 November 2003/ Accepted 23 November 2003

The long terminal repeat (LTR) transcriptional promoters of different human immunodeficiency virus (HIV) type 1 subtypes were inserted into the LAI molecular clone of subtype B. The viral genotypes represent seven subtypes (A, B, C, D, E, F, and G) and one circulating recombinant form (AG). We performed replication studies with this isogenic set of viruses across six cellular environments. This approach revealed strong cellular environment effects, but the method was not sensitive enough to detect small differences in the replication rate between the subtypes. By conducting pairwise competition experiments between the virus variants in six cellular environments, we could demonstrate significant differences in the replication rates of the subtypes and that LTR-determined viral fitness depends both on the host cell type and the activation state of the cell. In addition, we determined the degree of conservation of the transcription factor-binding sites (TFBS) in the different-subtype LTRs by analyzing sequences from the HIV sequence database. The sequence analyses revealed subtype-specific conservation of certain TFBS. The results indicate that one should consider the possibility of subtype-specific viral replication rates in vivo, which are strongly influenced by the host environment. We argue that the multidimensional host environment may have shaped the genetic structures of the subtype LTRs.

* Corresponding author. Mailing address: University of Amsterdam, Dept. of Human Retrovirology, Meibergdreef 15, Amsterdam 1105 AZ, The Netherlands. Phone: 31 20 566 4822. Fax: 31 20 691 6531. E-mail: b.berkhout{at}amc.uva.nl.

Journal of Virology, April 2004, p. 3675-3683, Vol. 78, No. 7
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.7.3675-3683.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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