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Journal of Virology, April 2000, p. 3740-3751, Vol. 74, No. 8
Department of Human Retrovirology, Academic
Medical Center, University of Amsterdam, Amsterdam, The Netherlands
Received 24 September 1999/Accepted 25 January 2000
The current human immunodeficiency virus type 1 (HIV-1) shows an
increasing number of distinct viral subtypes, as well as viruses that
are recombinants of at least two subtypes. Although no biological
differences have been described so far for viruses that belong to
different subtypes, there is considerable sequence variation between
the different HIV-1 subtypes. The HIV-1 long terminal repeat (LTR)
encodes the transcriptional promoter, and the LTR of subtypes A through
G was cloned and analyzed to test if there are subtype-specific
differences in gene expression. Sequence analysis demonstrated a unique
LTR enhancer-promoter configuration for each subtype. Transcription
assays with luciferase reporter constructs showed that all subtype LTRs
are functional promoters with a low basal transcriptional activity and
a high activity in the presence of the viral Tat transcriptional
activator protein. All subtype LTRs responded equally well to the Tat
trans activator protein of subtype B. This result suggests
that there are no major differences in the mechanism of Tat-mediated
trans activation among the subtypes. Nevertheless,
subtype-specific differences in the activity of the basal LTR promoter
were measured in different cell types. Furthermore, we measured a
differential response to tumor necrosis factor alpha treatment, and the
induction level correlated with the number of NF-
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Functional Differences between the Long Terminal Repeat
Transcriptional Promoters of Human Immunodeficiency Virus Type 1 Subtypes A through G
B sites in the
respective LTRs, which varies from one (subtype E) to three (subtype
C). In general, subtype E was found to encode the most potent LTR, and
we therefore inserted the core promoter elements of subtype E in the
infectious molecular clone of the LAI isolate (subtype B). This
recombinant LAI-E virus exhibited a profound replication advantage
compared with the original LAI virus in the SupT1 T-cell line,
indicating that subtle differences in LTR promoter activity can have a
significant impact on viral replication kinetics. These results suggest
that there may be considerable biological differences among the HIV-1 subtypes.
*
Corresponding author. Mailing address: Department of
Human Retrovirology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands. Phone: (31-20) 566 4822. Fax: (31-20) 691 6531. E-mail:
b.berkhout{at}amc.uva.nl.
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