A safe and effective human immunodeficiency virus type-1 (HIV-1) vaccine is urgently needed to stem worldwide AIDS pandemic, but still remains elusive. Among all the HIV-1 vaccine modalities examined thus far, nef-deleted live-attenuated HIV-1 vaccines (Δnef-LAV) confer the best protection against HIV-1 acquisition in simian immunodeficiency virus/rhesus macaque model of HIV-1 infection. However, safety concerns on Δnef-LAV preclude its clinical uses. We introduce a new synthetic chemical biology approach to control HIV-1 replication, which entails the manipulation of essential HIV-1 protein biosynthesis through unnatural amino acid-mediated suppression of genome-encoded blank codon (codon that do not encode a natural proteinogenic amino acid, such as nonsense triplet codon and frameshift codon). We successfully demonstrated that we could turn HIV-1 replication on and off in vitro. We also engineered HIV-1 genome and generated an HIV-1 mutant that contains a genomic copy of the special suppressor tRNA and aminoacyl-tRNA synthetase pair, which enables multi-cycle replication control and immunological evaluation in vivo. We envisaged that allowing Δnef-LAV to replicate only in the presence of unnatural amino acid would improve its safety while still maintains its good efficacy against HIV-1 acquisition. This new approach could be potentially applied to the generation of vaccines against other pathogenic viruses or bacteria.

New synthetic chemical biology approach for the development of HIV-1 vaccine

251st National Meeting (2016)

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