5 years ago

HIV-1 resistance to dolutegravir is affected by cellular histone acetyltransferase activity.

Wainberg MA, Brenner B, Anstett K, Mesplède T
Integrase strand transfer inhibitors are the newest class of antiretrovirals to have been approved for the treatment of HIV. Canonical resistance to these competitive inhibitors develops through substitutions in the integrase active site that disrupt drug-protein interactions. However resistance against the newest integrase inhibitor dolutegravir (DTG) is associated with a R263K substitution at the C-terminus of integrase that causes resistance through an unknown mechanism. The integrase C-terminal domain is involved in many processes over the course of infection and is post-translationally modified via acetylation of three lysine residues, that are important for enzyme activity, integrase multimerization, and protein-protein interactions. Here, we report that regulation of the acetylation of integrase is integral to the replication of HIV in the presence of DTG and that R263K specifically disrupts this regulation, likely due to enhancement of interactions with the histone deacetylase I complex, as suggested by co-immunoprecipitation. Although no detectable differences were observed in levels of cell-free acetylation of wild-type (WT) and mutated R263K enzymes, the inhibition of cellular histone acetyltransferase enzymes sensitized NL4.3WT viruses to DTG while NL4.3R263K was almost completely unaffected. When levels of endogenous acetylation were manipulated in virus-producing cells, inhibitors of acetylation enhanced the replication of NL4.3R263K whereas inhibition of deacetylation greatly diminished the replication of NL4.3WT Taken together, these results point to a pivotal role of acetylation in the resistance mechanism of HIV to some second-generation integrase strand transfer inhibitors such as DTG.IMPORTANCE This is, to our knowledge, the first report of the influence of post-translational modifications on HIV drug resistance. Both viral replication and resistance to second-generation integrase strand transfer inhibitors of both WT and INSTI-resistant HIV were differentially affected by acetylation, likely as a result of altered interactions between integrase and the cellular deacetylation machinery. Many "shock and kill" strategies to eradicate HIV manipulate endogenous levels of acetylation in order to reactivate latent HIV. However, our results suggest that some drug resistant viruses may differentially respond to such stimulation, which may complicate the attainment of this goal. Our future work will further illuminate the mechanisms involved.

Publisher URL: https://www.ncbi.nlm.nih.gov/pubmed/28835492

DOI: PubMed:28835492

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