Abstract

Despite significant advances in the treatment of human immunodeficiency virus type-1 (HIV) infection, antiretroviral therapy only suppresses viral replication but is unable to eliminate infection. Thus, discontinuation of antiretrovirals results in viral reactivation and disease progression. A major reservoir of HIV latent infection resides in resting central memory CD4+ T cells (TCM) that escape clearance by current therapeutic regimens and will require novel strategies for elimination. Here, we evaluated the therapeutic potential of autophagy-inducing peptides, Tat-Beclin 1 and Tat-vFLIP-α2, which can induce a novel Na+/K+-ATPase dependent form of cell death (autosis), to kill latently HIV-infected TCM while preventing virologic rebound. In this study, we encapsulated autophagy inducing peptides into biodegradable lipid-coated hybrid PLGA (poly lactic-co-glycolic acid) nanoparticles for controlled intracellular delivery. A single dose of nanopeptides was found to eliminate latent HIV infection in an in vitro primary model of HIV latency and ex vivo using resting CD4+ T cells obtained from peripheral blood mononuclear cells of HIV-infected patients on antiretroviral with fully suppressed virus for greater than 12 months. Notably, increased LC3B lipidation, SQSTM1/p62 degradation and Na+/K+-ATPase activity characteristic of autosis, were detected in nanopeptide treated latently HIV-infected cells compared to untreated uninfected or infected cells. Nanopeptide-induced cell death could be reversed by knockdown of autophagy proteins, ATG5 and ATG7, and inhibition or knockdown of Na+/K+-ATPase. Importantly, viral rebound was not detected following the induction of the Na+/K+-ATPase dependent form of cell death induced by the Tat-Beclin 1 and Tat-vFLIP-α2 nanopeptides. These findings provide a novel strategy to eradicate HIV latently infected resting memory CD4+ T cells, the major reservoir of HIV latency, through the induction of Na+/K+-ATPase dependent autophagy, while preventing reactivation of virus and new infection of uninfected bystander cells.

Highlights

  • At present, an estimated 37 million people live with human immunodeficiency virus type-1 (HIV) infection worldwide[1]

  • We further evaluated the potential of these nanoformulated autophagy-inducing peptides to kill latently HIV-infected central memory CD4+ T cells (HIVTCM)

  • We have previously shown the ability of lipid-coated hybrid PLGA nanoparticles loaded with Tat-viral FLIP (vFLIP)-α2 peptides to kill selectively HIV-infected macrophages[31]

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Summary

Introduction

An estimated 37 million people live with human immunodeficiency virus type-1 (HIV) infection worldwide[1]. The primary reservoirs of HIV latently infected cells are thought to be long-lived, resting central memory CD4+. T cells (TCM), which are established early in infection, harbor integrated proviral DNA, and fail to produce replication-competent virus[6,7,8]. These latently infected cells are not targeted by the immune system and ART is ineffective in eradicating the virus. The precise mechanisms that promote the long-term survival of HIV latently infected TCM are largely unknown, it is likely that cell death pathways are critical to cell survival, and that anti-apoptotic proteins and modulation of autophagy play an important role in prolonged cell survival.

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