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J. Biol. Chem., Vol. 276, Issue 34, 32184-32190, August 24, 2001
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From the An effective vaccine against AIDS is unlikely to
be available for many years. As we approach two decades since the first
identification of human immunodeficiency virus, type 1 (HIV-1),
currently, only one subunit vaccine candidate has reached phase 3 of
clinical trials. The subunit approach has been criticized for its
inability to elicit effectively cytotoxic T-lymphocyte (CTL) response,
which is felt by many to be needed for protection against HIV-1
infection. In subhuman primates, a live attenuated simian
immunodeficiency virus (SIV) vaccine candidate, capable of inducing
CTL, has been found to confer prophylactic immunity sufficient to
prevent simian AIDS. Because replication competent (live) attenuated
viruses could over time revert to virulence, such a live attenuated
approach has largely been dismissed for HIV-1. Here, we describe the
creation of constitutively dead conditionally live (CDCL) HIV-1
genomes. These genomes are constitutively defective for the Tat/TAR
axis and are conditionally dependent on tetracycline for attenuated replication with robust expression of viral antigens. Our results suggest that CDCL genomes merit consideration as safer "live" attenuated HIV-1 vaccine candidates.
Constitutively Dead, Conditionally Live HIV-1 Genomes
EX VIVO IMPLICATIONS FOR A LIVE VIRUS
VACCINE*
,,
, and
Saint Michael's Medical Center and the New
Jersey Medical School-University of Medicine and Dentistry of New
Jersey, Newark, New Jersey 07102, the § Tulane
Regional Primate Research Center, Covington, Louisiana 70433, the
¶ Aaron Diamond AIDS Research Center, The Rockefeller University,
New York, New York 10016, the Department of Pathology, George
Washington University School of Medicine, Washington, D. C. 20037, and
the ** Laboratory of Molecular Microbiology, NIAID, National Institutes
of Health, Bethesda, Maryland 20892
*
This work (with fellowship funding from The New
Jersey Medical School (to M. K.)) was supported in part by
National Institutes of Health Grant AI46316-02 (to S. M. S.) and by the Intramural AIDS Targeted Antiviral Program from
the Office of the Director, National Institutes of Health (to K. T. J.).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.
To whom correspondence should be addressed: NIH, Bldg. 4, Rm.
306, 9000 Rockville Pike, Bethesda, MD 20892-0460. Tel.: 301-496-6680; Fax: 301-480-3686; E-mail: kj7e@nih.gov.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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