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PLoS One. 2016 Apr 6;11(4):e0151572. doi: 10.1371/journal.pone.0151572. eCollection 2016.

Specific Elimination of Latently HIV-1 Infected Cells Using HIV-1 Protease-Sensitive Toxin Nanocapsules.

Author information

1
Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at University of California, University of California Los Angeles, Los Angeles, California, United States of America.
2
Department of Biomolecular and Chemical Engineering, University of California Los Angeles, Los Angeles, California, United States of America.
3
California NanoSystems Institute (CNSI), University of California Los Angeles, Los Angeles, California, United States of America.
4
Division of Hematology-Oncology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, United States of America.
5
UCLA AIDS Institute, Los Angeles, California, United States of America.

Abstract

Anti-retroviral drugs suppress HIV-1 plasma viremia to undetectable levels; however, latent HIV-1 persists in reservoirs within HIV-1-infected patients. The silent provirus can be activated through the use of drugs, including protein kinase C activators and histone deacetylase inhibitors. This "shock" approach is then followed by "kill" of the producing cells either through direct HIV-1-induced cell death or natural immune mechanisms. However, these mechanisms are relatively slow and effectiveness is unclear. Here, we develop an approach to specifically target and kill cells that are activated early in the process of virus production. We utilize a novel nanocapsule technology whereby the ricin A chain is encapsulated in an inactive form within a polymer shell. Specificity for release of the ricin A toxin is conferred by peptide crosslinkers that are sensitive to cleavage by HIV-1 protease. By using well-established latent infection models, J-Lat and U1 cells, we demonstrate that only within an HIV-1-producing cell expressing functional HIV-1 protease will the nanocapsule release its ricin A cargo, shutting down viral and cellular protein synthesis, and ultimately leading to rapid death of the producer cell. Thus, we provide proof of principle for a novel technology to kill HIV-1-producing cells without effects on non-target cells.

PMID:
27049645
PMCID:
PMC4822841
DOI:
10.1371/journal.pone.0151572
[Indexed for MEDLINE]
Free PMC Article

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