Challenging the HIV DNA integration dogma Integration-independent HIV replication to escape from integrase inhibitors

Like other retroviruses, human immunodeficiency virus (HIV) has an RNA genome that is converted into a linear DNA molecule upon infecting host cells. This viral DNA is then integrated into the host’s cellular DNA by the viral integrase and subsequently used for the production of new virus particles. Integrase inhibitors, such as dolutegravir (DTG), effectively block DNA integration and inhibit virus replication, and are therefore widely used in antiretroviral therapy. HIV typically escapes the effects of inhibitors by acquiring mutations in the gene encoding the targeted protein. Accordingly, mutations in the viral integrase have been linked to resistance to DTG. However, this thesis describes an alternative mechanism of DTG resistance involving mutations in the viral 3’-polypurine tract (3’PPT), an RNA sequence element that serves as a primer for the regular reverse transcription of HIV RNA into DNA. These mutations inactivate the 3’PPT element, leading to the production of circular, rather than linear, HIV DNA. This circular HIV DNA does not integrate into the host genome but still allows the production of new virus particles. As a result, the virus can replicate in the presence of integrase inhibitors, thereby reducing the effectiveness of these antivirals. Moreover, this integration-independent replication pathway challenges the prevailing dogma that integration is an essential step in retrovirus replication.