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J. Biol. Chem., Vol. 278, Issue 18, 15832-15841, May 2, 2003
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From the Centre de Recherche en Infectiologie, Hôpital CHUL,
Centre Hospitalier Universitaire de Québec, and
Département de Biologie Médicale, Faculté de
Médecine, Université Laval, Ste-Foy,
Québec G1V 4G2, Canada
Maternal-infant transmission of human
immunodeficiency virus type-1 (HIV-1) is the primary cause of this
retrovirus infection in neonates. Trophoblasts have been proposed to
play a critical role in modulating virus spread to the fetus. This
paper addresses the mechanism of HIV-1 biology in trophoblastic cells.
The trophoblastic cell lines BeWo, JAR, and JEG-3 were infected with
reporter HIV-1 particles pseudotyped with envelope glycoproteins from
the vesicular stomatitis virus or various strains of HIV-1. We
demonstrate that despite a high internalization process of HIV-1 and no
block in viral production, HIV-1 established a limited infection of
trophoblasts with the production of very few progeny viruses. The
factor responsible for this restriction to virus replication in such a
cellular microenvironment is that the intracellular p24 is concentrated
predominantly in endosomal vesicles following HIV-1 entry. HIV-1
transcription and virus production of infectious particles were both
augmented upon treatment of trophoblasts with tumor necrosis factor-
The Low Viral Production in Trophoblastic Cells Is Due to
a High Endocytic Internalization of the Human Immunodeficiency Virus
Type 1 and Can Be Overcome by the Pro-inflammatory Cytokines Tumor
Necrosis Factor-
and Interleukin-1*
§,
and interleukin-1. However, the amount of progeny virions released by
trophoblasts infected with native HIV-1 virions was so low even in the
presence of pro-inflammatory cytokines that a co-culture step with
indicator cells was necessary to detect virus production. Collectively
these data illustrate for the first time that the natural low
permissiveness of trophoblasts to productive HIV-1 infection is because
of a restriction in the mode of entry, and such a limitation can be
overcome with physiologic doses of tumor necrosis factor- and
interleukin-1, which are both expressed by the placenta, in conjunction
with cell-cell contact. Considering that there is a linear correlation
between viral load and HIV-1 vertical transmission, the environment may
thus contribute to the propagation of HIV-1 across the placenta.
*
This work was supported in part by Canadian Institutes of
Health Research HIV/AIDS Research Program Grant HOP-15575 (to
M. J. T.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Performed this work in partial fulfillment for the Ph.D. Degree in
the Program of Microbiology-Immunology, Faculty of Medicine, Laval University.
§
Recipient of Canadian Institutes of Health Research Doctoral
Research Awards from the HIV/AIDS Research Program.
¶
Holds a Tier 1 Canada Research Chair in Human
Immuno-Retrovirology. To whom correspondence should be addressed:
Laboratoire d'Immuno-Rétrovirologie Humaine, Centre de Recherche
en Infectiologie, RC709, Hôpital CHUL, Centre Hospitalier
Universitaire de Québec, 2705 Blvd. Laurier, Ste-Foy,
Québec G1V 4G2, Canada. Tel.: 418-654-2705; Fax: 418-654-2212;
E-mail: michel.j.tremblay@crchul.ulaval.ca.
Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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