PLGA-PEG Nanoparticles Coated with Anti-CD45RO and Loaded with HDAC Plus Protease Inhibitors Activate Latent HIV and Inhibit Viral Spread.

Xiaolong Tang,Xinkuang Liu,Chunmei Xie,Liang Liu,Shuyu Cai,Fujina Zhang,Shuping Zhou,Jia Wei,Yong Liang,Yongqiang Zhu,Wei Hou

doi:10.1186/s11671-015-1112-z

Abstract

Activating HIV-1 proviruses in latent reservoirs combined with inhibiting viral spread might be an effective anti-HIV therapeutic strategy. Active specific delivery of therapeutic drugs into cells harboring latent HIV, without the use of viral vectors, is a critical challenge to this objective. In this study, nanoparticles of poly(lactic-co-glycolic acid)-polyethylene glycol diblock copolymers conjugated with anti-CD45RO antibody and loaded with the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) and/or protease inhibitor nelfinavir (Nel) were tested for activity against latent virus in vitro. Nanoparticles loaded with SAHA, Nel, and SAHA + Nel were characterized in terms of size, surface morphology, zeta potential, entrapment efficiency, drug release, and toxicity to ACH-2 cells. We show that SAHA- and SAHA + Nel-loaded nanoparticles can target latently infected CD4+ T-cells and stimulate virus production. Moreover, nanoparticles loaded with SAHA + NEL were capable of both activating latent virus and inhibiting viral spread. Taken together, these data demonstrate the potential of this novel reagent for targeting and eliminating latent HIV reservoirs.

Highlights

HIV infection is associated with a very high viral load in the body leading to a progressive depletion of immune cells, CD4+ T cells [1, 2]
We investigated the change in histone deacetylase 4 (HDAC4) expression in ACH-2 cells incubated with scFv CD45RO-suberoylanilide hydroxamic acid (SAHA)/Nel NPs and scFv CD45RO-SAHA NPs
Our results showed a gradual reduction in HDAC4 mRNA and protein expression in cells treated with both scFv CD45RO-SAHA/Nel NPs and scFv CD45RO-SAHA NPs, reaching virtually undetectable levels after 24 h. (Fig. 5a, b)

Summary

Introduction

HIV infection is associated with a very high viral load in the body leading to a progressive depletion of immune cells, CD4+ T cells [1, 2]. The infection can be treated with highly active antiretroviral therapy (HAART) consisting of at least three drugs from at least two classes of antiretroviral agents [3]. HAART cannot eliminate latent HIV reservoirs in resting CD4+/CD45RO+ T memory (Tm) cells [3, 4, 6]. The best way to completely eliminate this reservoir is to reactivate latent HIV-1 by inducing proviral gene expression [5]. Gene expression is controlled partly by HDAC inhibitors (HDACi) such as vorinostat, known as suberoylanilide hydroxamic acid (SAHA), flush HIV out from reservoirs of latently infected cells by activating gene expression in proviruses [11, 12]. Concurrent treatment with an antiretroviral such as the protease inhibitor nelfinavir (Nel) and an HDACi

Methods

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Discussion

Conclusion