Despite being first identified more than three decades ago, the antisense gene of HIV-1 remains an enigma. is present uniquely in pandemic (group M) HIV-1 strains, and it is absent in all non-pandemic (out-of-M) HIV-1 strains and virtually all non-human primate lentiviruses. This suggests that the creation of may have contributed to HIV-1 fitness or worldwide spread. It also raises the question of which evolutionary processes were at play in the creation of . Here, we show that HIV-1 genomes containing an intact gene are associated with faster HIV-1 disease progression. Furthermore, we demonstrate that the creation of a full-length gene occurred via the evolution of codon usage in overlapping on the opposite strand. This involved differential use of synonymous codons or conservative amino acid substitution in that eliminated internal codons in , and redistribution of synonymous codons in that minimized the likelihood of new premature arising in . Nevertheless, the creation of a full-length gene reduced the genetic diversity of . The Luria-Delbruck fluctuation test suggests that the interrupted open reading frame (ORF) is the progenitor of the intact ORF, rather than a descendant under random genetic drift. Therefore, the existence of group-M isolates with a truncated ORF indicates an incomplete transition process. For the first time, our study links the presence of a full-length ORF to faster disease progression, thus warranting further investigation into the cellular processes and molecular mechanisms through which the ASP protein impacts HIV-1 replication, transmission, and pathogenesis.IMPORTANCEOverlapping genes engage in a tug-of-war, constraining each other's evolution. The creation of a new gene overlapping an existing one comes at an evolutionary cost. Thus, its conservation must be advantageous, or it will be lost, especially if the pre-existing gene is essential for the viability of the virus or cell. We found that the creation and conservation of the HIV-1 antisense gene occurred through differential use of synonymous codons or conservative amino acid substitutions within the overlapping gene, . This process did not involve amino acid changes in ENV that benefited its function, but rather it constrained the evolution of ENV. Nonetheless, the creation of brought a net selective advantage to HIV-1 because is conserved especially among high-prevalence strains. The association between the presence of an intact gene and faster HIV-1 disease progression supports that conclusion and warrants further investigation.