What data validates tRNA as a HIV drug target?
Sequence analysis of HIV genome collected from human isolates reveals that the primer binding site, PBS, is the most conserved region of the viral genome. The 18 nucleotides of the PBS are universally conserved in all mutants. Deletion of the PBS blocks the ability of the mutant to replicate in culture; thus, one can infer that blocking the PBS with a therapeutic compound would also be lethal to HIV. Mutation of the site by transferring the priming function to another tRNA results in poor viral transcription within the infected cell and marked loss in the ability to form infectious particles. All of the PBS mutants quickly revert back to tRNA lysine by selective mutation. Validation that the disruption of the PBS complex disrupts viral function has been demonstrated both by use of antisense oligonucleotides and siRNA.
