The existence of an HIV-1 protein translated from an antisense transcript was suggested over 25 years ago. However, this Antisense Protein (ASP) gene has still not been completely accepted by the HIV-1 research community. The aim of this review is to discuss recent findings, which suggest that ASP needs to be considered as a viral gene, playing an important role in HIV-1 replication and persistence. In past years, several studies have highlighted the existence of HIV-1 antisense transcripts. More recently, we and others have convincingly demonstrated that this transcript produces a protein with a unique distribution and a rapid turnover, when expressed in mammalian cells. Furthermore, a role in autophagy and HIV-1 replication has been associated with this protein. In light of these recent reports, we believe that ASP needs to be added to the schematic representation of the HIV-1 proviral DNA and requires further investigation, as it could represent a new potential target for anti-retroviral therapies and vaccine strategies.