A safe and effective vaccine against human immunodeficiency virus type 1 (HIV‐1) is urgently needed to combat the worldwide AIDS pandemic, but still remains elusive. The fact that uncontrolled replication of an attenuated vaccine can lead to regaining of its virulence creates safety concerns precluding many vaccines from clinical application. We introduce a novel approach to control HIV‐1 replication, which entails the manipulation of essential HIV‐1 protein biosynthesis through unnatural amino acid (UAA*)‐mediated suppression of genome‐encoded blank codon. We successfully demonstrate that HIV‐1 replication can be precisely turned on and off in vitro.