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Type 1-programmed dendritic cells drive antigen-specific latency reversal and immune elimination of persistent HIV-1
BACKGROUND: Despite the success of antiretroviral therapy (ART), latent HIV-1 continues to persist in a long-lived population of resting memory CD4(+) T cells within those who are infected. Finding a safe and effective means to induce latency reversal (LR) during ART to specifically expose this late...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6557749/ https://www.ncbi.nlm.nih.gov/pubmed/30952614 http://dx.doi.org/10.1016/j.ebiom.2019.03.077 |
Sumario: | BACKGROUND: Despite the success of antiretroviral therapy (ART), latent HIV-1 continues to persist in a long-lived population of resting memory CD4(+) T cells within those who are infected. Finding a safe and effective means to induce latency reversal (LR) during ART to specifically expose this latent HIV-1 cellular reservoir for immune elimination has been a major barrier to a functional cure. METHODS: In this study, we test the use of antigen-presenting type 1-polarized, monocyte-derived dendritic cells (MDC1) generated from chronic HIV-1-infected individuals on ART as a means to induce HIV-1 latency reversal in autologous CD4(+) T cells harboring replication-competent provirus. We use the same MDC1 for ex-vivo generation of autologous HIV-1 antigen-specific CD8(+) cytotoxic T cells (CTL) and test their effector responses against the MDC1-exposed HIV-1- infected CD4(+) T cell targets. FINDINGS: MDC1 presentation of either HIV-1 or cytomegalovirus (CMV) antigens to CD4(+) T cells facilitated HIV-1 LR. This antigen-driven MDC1-mediated LR was sharply diminished with blockade of the CD40L/CD40 ‘helper’ signaling pathway. Importantly, these antigen-presenting MDC1 also activated the expansion of CTL capable of killing the exposed HIV-1-infected targets. INTERPRETATION: Inclusion of virus-associated MHC class II ‘helper’ antigens in MDC1-based HIV-1 immunotherapies could serve both as a targeted means to safely unmask antigen-specific CD4(+) T cells harboring HIV-1, and to support CTL responses that can effectively target the MDC1-exposed HIV-1 cellular reservoir as a functional cure strategy. FUND: This study was supported by the NIH-NAID grants R21-AI131763, U01-AI35041, UM1-AI126603, and T32-AI065380. |
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