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Antimicrob Agents Chemother. 2015 Jul;59(7):3984-94. doi: 10.1128/AAC.00574-15. Epub 2015 Apr 20.

Histone deacetylase inhibitor romidepsin inhibits de novo HIV-1 infections.

Author information

1
Institute of Biomedicine, Faculty of Health, Aarhus University, Aarhus, Denmark Aarhus Research Centre of Innate Immunology, Aarhus, Denmark.
2
Department of Infectious Diseases, Aarhus University Hospital Skejby, Aarhus, Denmark Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark.
3
Department of Infectious Diseases, Aarhus University Hospital Skejby, Aarhus, Denmark.
4
Institute of Biomedicine, Faculty of Health, Aarhus University, Aarhus, Denmark.
5
Department of Infectious Diseases, Aarhus University Hospital Skejby, Aarhus, Denmark Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark Aarhus Institute for Advanced Studies, Aarhus University, Aarhus, Denmark pauden@rm.dk mrj@biomed.au.dk.
6
Institute of Biomedicine, Faculty of Health, Aarhus University, Aarhus, Denmark Aarhus Research Centre of Innate Immunology, Aarhus, Denmark pauden@rm.dk mrj@biomed.au.dk.

Abstract

Adjunct therapy with the histone deacetylase inhibitor (HDACi) romidepsin increases plasma viremia in HIV patients on combination antiretroviral therapy (cART). However, a potential concern is that reversing HIV latency with an HDACi may reactivate the virus in anatomical compartments with suboptimal cART concentrations, leading to de novo infection of susceptible cells in these sites. We tested physiologically relevant romidepsin concentrations known to reactivate latent HIV in order to definitively address this concern. We found that romidepsin significantly inhibited HIV infection in peripheral blood mononuclear cells and CD4(+) T cells but not in monocyte-derived macrophages. In addition, romidepsin impaired HIV spreading in CD4(+) T cell cultures. When we evaluated the impact of romidepsin on quantitative viral outgrowth assays with primary resting CD4(+) T cells, we found that resting CD4(+) T cells exposed to romidepsin exhibited reduced proliferation and viability. This significantly lowered assay sensitivity when measuring the efficacy of romidepsin as an HIV latency reversal agent. Altogether, our data indicate that romidepsin-based HIV eradication strategies are unlikely to reseed a latent T cell reservoir, even under suboptimal cART conditions, because romidepsin profoundly restricts de novo HIV infections.

PMID:
25896701
PMCID:
PMC4468708
DOI:
10.1128/AAC.00574-15
[Indexed for MEDLINE]
Free PMC Article

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