Oral abstracts of the HIV Cure and Reservoir Symposium 2017
نویسندگان
چکیده
Background: Persistence of latent provirus is the main barrier towards a cure for HIV. We propose a novel strategy to reduce the HIV reservoir by drug-induced retargeting of HIV integration. A novel class of integration inhibitors, LEDGINs, inhibits the interaction between HIV integrase (IN) and the LEDGF/p75 cofactor, the main determinant of integration site selection. This results in an allosteric inhibition of HIV IN (early effect). Moreover, when present during production, progeny virus displays morphological and replication irregularities (late effect). Methods: Integration sites were sequenced using 454 pyrosequencing. To evaluate reactivation potential, cell lines were infected with a double-reporter virus and LEDGIN was added during infection (early effect) or during production of the virus (late effect). Cells were reactivated and analyzed by FACS. In a multiple round experiment, primary activated CD4+ T cells were infected with wild type NL4.3 virus in the presence of LEDGIN or RAL. Cells were reactivated and virus production was measured by p24 ELISA. Results and conclusions: LEDGIN-mediated inhibition of the LEDGF/p75-IN interaction blocks replication and relocates integration out of transcription units. This retargeting resulted in a residual reservoir that contains up to 95% of latent cells that are resistant to reactivation. In activated CD4+ T-cells, both LEDGIN and RAL reduced infection. The residual provirus established under LEDGIN treatment was hampered for reactivation, a phenotype not observed with RAL. Addition of LEDGINs early during acute infection does affect the formation of the latent reservoir. Bringing the majority of residual proviruses in a state of deep latency and defective for reactivation might represent an attractive approach to achieve an HIV remission.
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