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HIV-1 group O (HIV-O) is a rare variant that is characterized by a high number of natural polymorphisms in the integrase coding region that may impact on susceptibility to integrase strand transfer inhibitors (INSTIs) and on the emergence of resistance substitutions. We previously reported that HIV-O is more susceptible to RAL than HIV-1 group M (HIV-M).The aim of this study was to assess pathways of resistance to INSTIs in group 0 variants. Accordingly, we selected for resistance to each of raltegravir (RAL), elvitegravir (EVG), and dolutegravir (DTG) in cord blood mononuclear cells using HIV group O subtypes A and B, an HIV-O divergent isolate, and HIV-1 group M (subtype B, which served as a reference). Site-directed mutagenesis was performed on the pCOM2.5 HIV group 0 infectious clone to ascertain the impact of INSTI resistance substitutions at positions Q148R, N155H, and R263K within integrase on susceptibility to INSTIs and infectiousness.Cell culture selections of group O variants yielded similar patterns of resistance to RAL, EVG, and DTG as observed for subtype B. In the DTG selections, subtype B yielded S153Y, whereas a natural S153A polymorphism sometimes led to A153V in group O. The pCMO2.5/Q148R and pCMO2.5/N155H variants displayed far higher levels of resistance to DTG (>1000 FC) than was seen for group M viruses.HIV-O harboring Q148R and N155H shows higher resistance to DTG compared with HIV-M subtype B.