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EBioMedicine. 2019 May;43:295-306. doi: 10.1016/j.ebiom.2019.03.077. Epub 2019 Apr 2.

Type 1-programmed dendritic cells drive antigen-specific latency reversal and immune elimination of persistent HIV-1.

Author information

1
Department of Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, PA 15261, United States of America.
2
Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15261, United States of America.
3
Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, United States of America.
4
Department of Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, PA 15261, United States of America; Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261, United States of America.
5
Department of Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, PA 15261, United States of America. Electronic address: rbm19@pitt.edu.

Abstract

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.

KEYWORDS:

CD40 ligand; Cytomegalovirus; Dendritic cells; HIV-1 latency reversal; Immunotherapy; T cells

PMID:
30952614
PMCID:
PMC6557749
DOI:
10.1016/j.ebiom.2019.03.077
[Indexed for MEDLINE]
Free PMC Article

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