Abstract
The central function of the retroviral integrase protein (IN) is to catalyze the integration of viral DNA into the host genome to form the provirus. The IN protein has also been reported to play a role in a number of other processes throughout the retroviral life cycle such as reverse transcription, nuclear import and particle morphogenesis. Studies have shown that HIV-1 IN is subject to multiple post-translational modifications (PTMs) including acetylation, phosphorylation and SUMOylation. However, the importance of these modifications during infection has been contentious. In this study we attempt to clarify the role of acetylation of HIV-1 IN during the retroviral life cycle. We show that conservative mutation of the known acetylated lysine residues has only a modest effect on reverse transcription and proviral integration efficiency in vivo. However, we observe a large defect in successful expression of proviral genes at early times after infection by an acetylation-deficient IN mutant that cannot be explained by delayed integration dynamics. We demonstrate that the difference between the expression of proviruses integrated by an acetylation mutant and WT IN is likely not due to altered integration site distribution but rather directly due to a lower rate of transcription. Further, the effect of the IN mutation on proviral gene expression is independent of the Tat protein or the LTR promoter. At early times after integration when the transcription defect is observed, the LTRs of proviruses integrated by the mutant IN have altered histone modifications as well as reduced IN protein occupancy. Over time as the transcription defect in the mutant virus diminishes, histone modifications on the WT and mutant proviral LTRs reach comparable levels. These results highlight an unexpected role for the IN protein in regulating proviral transcription at early times post-integration.
Highlights
A key component of a successful retroviral infection is the integration of the proviral genome into the host cell genome
We examined the consequences of mutations preventing the acetylation of the IN protein on the retroviral life cycle
We uncovered a novel function for HIV-1 IN in regulating proviral transcription at early times after infection
Summary
A key component of a successful retroviral infection is the integration of the proviral genome into the host cell genome. The irreversible process of retroviral integration is imperative for maintenance of infection as it establishes a stable template for proviral transcription and continued viral replication. Integration establishes the provirus as an inextricable component of the host genome, which is a major barrier to treatment and cure of retroviral infections. A dinucleotide is cleaved from the 3’ strand at either LTR end exposing a 3’-hydroxyl group that subsequently attacks the host target DNA during the joining process. This leaves a gapped DNA with viral overhangs that must subsequently be repaired by host enzymes [1]
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