CXCR4 Targeting Nanoplatform for Transcriptional Activation of Latent HIV-1 Infected T Cells

초록

Antiretroviraldrugs are limited in their ability to target latentretroviral reservoirs in CD4+ T cells, highlighting the need for aT cell-targeted drug delivery system that activates the transcriptionof inactivated viral DNA in infected cells. Histone deacetylase inhibitors(HDACi) disrupt chromatin-mediated silencing of the viral genome andare explored in HIV latency reversal. But single drug formulationsof HDACi are insufficient to elicit therapeutic efficacy, warrantingcombination therapy. Furthermore, protein kinase C activators (PKC)have shown latency reversal activity in HIV by activating the NF-& kappa;Bsignaling pathway. Combining HDACi (SAHA) with PKC (PMA) activatorsenhances HIV reservoir activation by promoting chromatin decondensationand subsequent transcriptional activation. In this study, we developeda mixed nanomicelle (PD-CR4) drug delivery system for simultaneoustargeting of HIV-infected CD4+ T cells with two drugs, suberoylanilidehydroxamic acid (SAHA) and phorbol 12-myristate 13-acetate (PMA).SAHA is a HDACi that promotes chromatin decondensation, while PMAis a PKC agonist that enhances transcriptional activation. The physicochemicalproperties of the formulated PD-CR4 nanoparticles were characterizedby NMR, CMC, DLS, and TEM analyses. Further, we investigated in vitrosafety profiles, targeting efficacy, and transcriptional activationof inactivated HIV reservoir cells. Our results suggest that we successfullyprepared a targeted PD system with dual drug loading. We have comparedlatency reversal efficacy of a single drug nanoformulation and combinationdrug nanoformulation. Final PD-SP-CR4 successfully activated infectedCD4+ T cell reservoirs and showed enhanced antigen release from HIVreservoir T cells, compared with the single drug treatment group asexpected. To summarize, our data shows PD-SP-CR4 has potential T celltargeting efficiency and efficiently activated dormant CD4+ T cells.Our data indicate that a dual drug-loaded particle has better therapeuticefficacy than a single loaded particle as expected. Hence, PD-CR4can be further explored for HIV therapeutic drug delivery studies.

키워드