Journal
EBIOMEDICINE
Volume 8, Issue -, Pages 248-264Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ebiom.2016.04.039
Keywords
HIV latency; HIV remission; Integration; LEDGIN; LEDGF/p75
Funding
- Flemish Fund for Scientific Research (FWO
- Fonds voor Wetenschappelijk Onderzoek)
- FWO
- KU Leuven Research Council (OT) [OT/13/098]
- HIV-ERA EURECA (IWT-SBO-EURECA) [ZL345530]
- KU Leuven IDO program [IDO/12/008]
- Belgian IAP Belvir [ZKC4893 - P7/45-P]
- Creative and Novel Ideas in HIV Research Program (CNIHR) [P30-AI027763, P30 AI027763]
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Persistence of latent, replication-competent Human Immunodeficiency Virus type 1 (HIV-1) provirus is the main impediment towards a cure for HIV/AIDS (Acquired Immune Deficiency Syndrome). Therefore, different therapeutic strategies to eliminate the viral reservoirs are currently being explored. We here propose a novel strategy to reduce the replicating HIV reservoir during primary HIV infection by means of drug-induced retargeting of HIV integration. A novel class of integration inhibitors, referred to as LEDGINs, inhibit the interaction between HIV integrase and the LEDGF/p75 host cofactor, the main determinant of lentiviral integration site selection. We show for the first time that LEDGF/p75 depletion hampers HIV-1 reactivation in cell culture. Next we demonstrate that LEDGINs relocate and retarget HIV integration resulting in a HIV reservoir that is refractory to reactivation by different latency-reversing agents. Taken together, these results support the potential of integrase inhibitors that modulate integration site targeting to reduce the likeliness of viral rebound. (C) 2016 The Authors. Published by Elsevier B.V.
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