Live attenuated AIDS viruses as vaccines: promise or peril?

Live attenuated viruses can provide vaccine protection against various viral illnesses. A number of live attenuated strains of the simian immunodeficiency virus (SIV) or related lentiviruses have been evaluated in primate models as vaccine candidates against AIDS. Impressive efficacy was observed for some viruses, most notably SIV strains with deletions in the nef-gene. Sterilizing immunity was seen against homologous and heterologous virus challenge, against cell-free and cell-associated challenge, against intravenous and mucosal challenge, and against challenge as early as 3 weeks and as late as 2.25 years after just one immunization. However, these promising efficacy results are overshadowed by safety problems, such as reversion of the vaccine strain to a pathogenic virus encoding full-length nef or residual virulence of multiply deleted vaccine strains. Strategies aimed at decreasing the replicative capacity of nef-deleted vaccine strains to increase the safety profile have significantly curtailed vaccine efficacy. Nevertheless, studies of live attenuated vaccine strains should proceed and should focus on determining the correlates of vaccine protection and the molecular determinants for virulence and attenuation.