Constitutively dead, conditionally live HIV-1 genomes. Ex vivo implications for a live virus vaccine.
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.
Smith
S M
SM
Saint Michael's Medical Center and the New Jersey Medical School-University of Medicine and Dentistry of New Jersey, Newark, New Jersey 07102, USA.
Khoroshev
M
M
Marx
P A
PA
Orenstein
J
J
Jeang
K T
KT
D016915:AIDS Vaccines; D001483:Base Sequence; D002460:Cell Line; D004279:DNA, Viral; D004318:Doxycycline / Q000494:pharmacology; D005822:Genetic Vectors; D016679:Genome, Viral; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D012689:Sequence Homology, Nucleic Acid; D013752:Tetracycline / Q000494:pharmacology; D014779:Virus Replication
D016915:AIDS Vaccines; D004279:DNA, Viral; D013752:Tetracycline; D004318:Doxycycline