Live-attenuated SIVdeltaNef provides solid protection against homologous challenge in the macaque model, although the correlates of protection have not been identified yet. Nevertheless, such an attenuated HIV-1 variant is not considered for further vaccine development because of safety considerations. The attenuated virus causes a chronic infection and the virus may evolve to regain pathogenicity. We made conditionally live HIV-1 and SIV variants that are dependent on doxycycline for replication. These viruses can be turned on and off at will, and could eventually become the next generation of live-attenuated vaccines.
We performed the first tests in macaques with the doxycycline-dependent SIV-rtTA variant. This virus replicates in vivo and demonstrates a partial vaccine effect upon wt SIVmac239 challenge in 8 of 8 animals, with a viral load reduction of 2 to 7 logs. Two of the 8 animals are fully protected and these animals exhibit a typical viral load shoulder of the vaccine strain. Intriguingly, these two animals pick up an identical mutation in the introduced rtTA gene that may provide immune-escape properties to the virus. Similar vaccine protection was observed in animals that continuously received doxycycline versus animals that received doxycycline for 6 months, but not the 8 weeks before challenge. These results demonstrate that persistent replication of the vaccine strain is not necessary for protection, suggesting that induction windows much shorter than 6 months may suffice.