期刊
AUTOPHAGY
卷 14, 期 8, 页码 1359-1375出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/15548627.2018.1476014
关键词
Autophagic cell death; autophagy-inducing peptide; autosis; chronic HIV infection; HIV preferential killing; HIV reservoir; Tat-Beclin 1; Tat-vFLIP
类别
资金
- National Institute of Neurological Disorders and Stroke of the NIH [R01 NS084912, R01 NS104015]
- HHS \ NIH \ National Institute of Neurological Disorders and Stroke (NINDS) [R01 NS084912, R01 NS104015]
- International Maternal Pediatric Adolescent AIDS Clinical Trials Network (SAS)
- National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) [UM1AI068632, UM1AI068616, UM1AI106716]
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
- National Institute of Mental Health (NIMH)
- HHS \ NIH \ National Institute of Allergy and Infectious Diseases (NIAID) [UM1AI068632, UM1AI106716]
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [UM1AI069536, UM1AI068616, UM1AI068632, UM1AI106716] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS104015, R01NS084912] Funding Source: NIH RePORTER
Although antiretroviral therapy is highly effective in suppressing human immunodeficiency virus type-1 (HIV) replication, treatment has failed to eliminate viral reservoirs and discontinuation of treatment results in viral reactivation. Here, we demonstrate that peptides Tat-vFLIP-alpha 2 and Tat-Beclin 1/BECN1 which have been shown to induce a Na+/K+-ATPase- and a macroautophagy/autophagy-dependent form of cell death, autosis, can preferentially kill HIV-infected macrophages while preventing virological rebound. To improve bioavailability and drug delivery, Tat-vFLIP-alpha 2 was encapsulated into biodegradable PLGA (poly lactic-co-glycolic acid)-lipid-PEG (polyethylene glycol) nanoparticles for long-lasting intracellular delivery. After a single dose of NP-vFLIP-alpha 2, HIV-infected macrophages were preferentially killed in a dose-dependent manner compared to uninfected or untreated HIV-infected cells with complete inhibition of HIV infection at 10 mu M of peptide. HIV-infected macrophages treated with NP-vFLIP-alpha 2 exhibited increased markers of autophagy including LC3B lipidation, SQSTM1/p62 degradation and Na+/K+-ATPase expression compared to untreated uninfected or infected cells. Moreover, the increased cell death observed in HIV-infected cells was not altered by treatment with bafilomycin A(1) (BAF) or the caspase inhibitor Z-VAD-FMK, but could be reversed following treatment with the Na+/K+-ATPase inhibitor, digoxin, or knockdown of ATG5 or ATG7. NP-vFLIP-alpha 2 induced preferential killing was also detected in HIV-infected macrophages under antiretroviral suppression without inducing viral reactivation. Additionally, we found that Na+/K+-ATPase was upregulated in HIV-infected cells, which enhanced NP-vFLIP-alpha 2 induced cell death. These findings provide a novel strategy to eradicate HIV-infected macrophages by selectively killing infected cells through the induction of Na+/K+-ATPase dependent autophagy, while preventing reactivation of virus and new infection of uninfected bystander cells.
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