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 year s. As we approach two decades since the first identification of human immun odeficiency virus, type 1 (HIV-1), currently, only one subunit vaccine cand idate 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 H IV-1 infection. In subhuman primates, a live attenuated simian immunodefici ency 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 H IV-1. Here, we describe the creation of constitutively dead conditionally l ive (CDCL) HIV-1 genomes. These genomes are constitutively defective for th e Tat/TAR axis and are conditionally dependent on tetracycline for attenuat ed replication with robust expression of viral antigens. Our results sugges t that CDCL genomes merit consideration as safer "live" attenuated HIV-1 va ccine candidates.