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Selective cell death of latently HIV-infected CD4⁺ T cells mediated by autosis inducing nanopeptides.

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 (T_CM) 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-?2, which can induce a novel Na⁺/K⁺-ATPase dependent form of cell death (autosis), to kill latently HIV-infected T_CM 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-?2 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.

SUBMITTER: Zhang G

PROVIDER: S-EPMC6541658 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Selective cell death of latently HIV-infected CD4+ T cells mediated by autosis inducing nanopeptides.

Zhang Gang G Luk Brian T BT Wei Xiaoli X Campbell Grant R GR Fang Ronnie H RH Zhang Liangfang L Spector Stephen A SA

Cell death & disease 20190529 6

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 fo ...[more]

PMID: 31142734

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Project description:The main obstacle to cure HIV-1 is the latent reservoir. Antiretroviral therapy effectively controls viral replication, however, it does not eradicate the latent reservoir. Latent CD4+ T cells are extremely rare in HIV-1 infected patients, making primary CD4+ T cell models of HIV-1 latency key to understanding latency and thus finding a cure. In recent years several primary CD4+ T cell models of HIV-1 latency were developed to study the underlying mechanism of establishing, maintaining and reversing HIV-1 latency. In the search of biomarkers, primary CD4+ T cell models of HIV-1 latency were used for bulk and single-cell transcriptomics. A wealth of information was generated from transcriptome analyses of different primary CD4+ T cell models of HIV-1 latency using latently- and reactivated HIV-1 infected primary CD4+ T cells. Here, we performed a pooled data-analysis comparing the transcriptome profiles of latently- and reactivated HIV-1 infected cells of 5 in vitro primary CD4+ T cell models of HIV-1 latency and 2 ex vivo studies of reactivated HIV-1 infected primary CD4+ T cells from HIV-1 infected individuals. Identifying genes that are differentially expressed between latently- and reactivated HIV-1 infected primary CD4+ T cells could be a more successful strategy to better understand and characterize HIV-1 latency and reactivation. We observed that natural ligands and coreceptors were predominantly downregulated in latently HIV-1 infected primary CD4+ T cells, whereas genes associated with apoptosis, cell cycle and HLA class II were upregulated in reactivated HIV-1 infected primary CD4+ T cells. In addition, we observed 5 differentially expressed genes that co-occurred in latently- and reactivated HIV-1 infected primary CD4+ T cells, one of which, MSRB2, was found to be differentially expressed between latently- and reactivated HIV-1 infected cells. Investigation of primary CD4+ T cell models of HIV-1 latency that mimic the in vivo state remains essential for the study of HIV-1 latency and thus providing the opportunity to compare the transcriptome profile of latently- and reactivated HIV-1 infected cells to gain insights into differentially expressed genes, which might contribute to HIV-1 latency.

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Selective cell death of latently HIV-infected CD4⁺ T cells mediated by autosis inducing nanopeptides.

Publications

Selective cell death of latently HIV-infected CD4<sup>+</sup> T cells mediated by autosis inducing nanopeptides.

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