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Article Dans Une Revue Journal of Virology Année : 2022

Mutations in the 3'-PPT Lead to HIV-1 Replication without Integration

Enzo Tramontano

Résumé

Integration of the reverse-transcribed genome is a critical step of the retroviral life cycle. Strand-transfer inhibitors (INSTIs) used for antiretroviral therapy inhibit integration but can lead to resistance mutations in the integrase gene, the enzyme involved in this reaction. A significant proportion of INSTI treatment failures, particularly those with second-generation INSTIs, show no mutation in the integrase gene. Here, we show that replication of a selected dolutegravir-resistant virus with mutations in the 3'-PPT (polypurine tract) was effective, although no integrated viral DNA was detected, due to the accumulation of unintegrated viral DNA present as 1-LTR circles. Our results show that mutation in the 3'-PPT leads to 1-LTR circles and not linear DNA as classically reported. In conclusion, our data provide a molecular basis to explain a new mechanism of resistance to INSTIs, without mutation of the integrase gene and highlights the importance of unintegrated viral DNA in HIV-1 replication. IMPORTANCE Our work highlights the role of HIV-1 unintegrated viral DNA in viral replication. A virus, resistant to strand-transfer inhibitors, has been selected in vitro. This virus highlights a mutation in the 3'PPT region and not in the integrase gene. This mutation modifies the reverse transcription step leading to the accumulation of 1-LTR circles and not the linear DNA. This accumulation of 1-LTR circles leads to viral replication without integration of the viral genome.
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Dates et versions

hal-03826878 , version 1 (24-10-2022)

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Clémence Richetta, Frédéric Subra, Isabelle Malet, Hervé Leh, Charlotte Charpentier, et al.. Mutations in the 3'-PPT Lead to HIV-1 Replication without Integration. Journal of Virology, 2022, 96, ⟨10.1128/jvi.00676-22⟩. ⟨hal-03826878⟩
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