HIV-1 3΄ polypurine tract mutations and integrase inhibitor resistance

The WHO recommends the use of the integrase strand transfer inhibitor (INSTI) dolutegravir for first-line antiretroviral therapy (ART) in all adults living with HIV infection. Although dolutegravir-based ART is well tolerated and effective, mutations in the integrase-encoding region of HIV-1 pol that confer resistance to dolutegravir can undermine treatment efficacy. An alternative pathway to dolutegravir resistance has also been described involving mutations in the 3΄ polypurine tract (3΄PPT), an RNA sequence element known to be important for retroviral reverse transcription and integration. The possible emergence of dolutegravir resistance mutations outside of integrase carries important ramifications for people receiving INSTI-based interventions. In this review, we assess the state of the literature pertaining to mutations in the 3΄PPT of HIV-1 and the potential of such mutations to confer INSTI resistance. We interpret these findings within the larger background of work that informs our understanding of reverse transcription, integration, and the expression of unintegrated DNA (uDNA) in HIV-1-infected cells. We also discuss technical complications that arise as a result of uDNA expression in culture-based drug susceptibility assays, and critically evaluate the supporting evidence for current models of 3΄PPT mutant replication. We conclude by proposing additional studies to determine the role of the 3΄PPT in clinical HIV-1 drug resistance.