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A Subset of Latency-Reversing Agents Expose HIV-Infected Resting CD4+ T-Cells to Recognition by Cytotoxic T-Lymphocytes
- Source :
- PLoS Pathogens, Vol 12, Iss 4, p e1005545 (2016), PLoS Pathogens, Public Library of Science
- Publication Year :
- 2016
- Publisher :
- Public Library of Science (PLoS), 2016.
-
Abstract
- Resting CD4⁺ T-cells harboring inducible HIV proviruses are a critical reservoir in antiretroviral therapy (ART)-treated subjects. These cells express little to no viral protein, and thus neither die by viral cytopathic effects, nor are efficiently cleared by immune effectors. Elimination of this reservoir is theoretically possible by combining latency-reversing agents (LRAs) with immune effectors, such as CD8⁺ T-cells. However, the relative efficacy of different LRAs in sensitizing latently-infected cells for recognition by HIV-specific CD8⁺ T-cells has not been determined. To address this, we developed an assay that utilizes HIV-specific CD8⁺ T-cell clones as biosensors for HIV antigen expression. By testing multiple CD8⁺ T-cell clones against a primary cell model of HIV latency, we identified several single agents that primed latently-infected cells for CD8⁺ T-cell recognition, including IL-2, IL-15, two IL-15 superagonists (IL-15SA and ALT-803), prostratin, and the TLR-2 ligand Pam₃CSK₄. In contrast, we did not observe CD8⁺ T-cell recognition of target cells following treatment with histone deacetylase inhibitors or with hexamethylene bisacetamide (HMBA). In further experiments we demonstrate that a clinically achievable concentration of the IL-15 superagonist ‘ALT-803’, an agent presently in clinical trials for solid and hematological tumors, primes the natural ex vivo reservoir for CD8⁺ T-cell recognition. Thus, our results establish a novel experimental approach for comparative evaluation of LRAs, and highlight ALT-803 as an LRA with the potential to synergize with CD8⁺ T-cells in HIV eradication strategies.<br />United States. National Institutes of Health (AI111860)
- Subjects :
- RNA viruses
CD4-Positive T-Lymphocytes
0301 basic medicine
Enzyme-Linked Immunospot Assay
HIV Infections
Pathology and Laboratory Medicine
Polymerase Chain Reaction
White Blood Cells
chemistry.chemical_compound
Spectrum Analysis Techniques
0302 clinical medicine
Immunodeficiency Viruses
Animal Cells
Virus latency
Medicine and Health Sciences
Cytotoxic T cell
Enzyme-Linked Immunoassays
lcsh:QH301-705.5
T Cells
ELISPOT
Flow Cytometry
Viral Persistence and Latency
Virus Latency
3. Good health
Medical Microbiology
Spectrophotometry
Viral Pathogens
030220 oncology & carcinogenesis
Viruses
Infectious diseases
Cytophotometry
Cellular Types
Pathogens
Research Article
lcsh:Immunologic diseases. Allergy
Immune Cells
Recombinant Fusion Proteins
Immunology
Cytotoxic T cells
Enzyme-Linked Immunosorbent Assay
Viral diseases
Biology
Research and Analysis Methods
Antiviral Agents
Microbiology
Hexamethylene bisacetamide
03 medical and health sciences
Immune system
Antigen
Virology
Retroviruses
Genetics
medicine
Humans
Molecular Biology Techniques
Immunoassays
Prostratin
Microbial Pathogens
Molecular Biology
Blood Cells
Lentivirus
Organisms
Biology and Life Sciences
HIV
Proteins
Cell Biology
medicine.disease
030104 developmental biology
chemistry
lcsh:Biology (General)
Immunologic Techniques
Virus Activation
Parasitology
lcsh:RC581-607
CD8
Cloning
T-Lymphocytes, Cytotoxic
Subjects
Details
- Language :
- English
- ISSN :
- 15537374 and 15537366
- Volume :
- 12
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- PLoS Pathogens
- Accession number :
- edsair.doi.dedup.....b637bb7e39d2d1446d31c920516cf548