Abstract
Purpose of ReviewFor most people living with HIV (PLWH), treatment with effective antiretroviral therapy (ART) results in suppression of viremia below the limit of detection of clinical assays, immune reconstitution, reduced immune activation, avoidance of opportunistic infections, and progression to AIDS. However, ART alone is not curative, and HIV persists in a non-replicating, latent form. In this review, we provide a historical perspective on non-specific latency reversal approaches (LRA 1.0) and summarize recent advances in latency reversal strategies that target specific signaling pathways within CD4+ T cells or other immune cells to induce expression of latent HIV (immune-based latency reversal, or LRA 2.0).Recent FindingsThe HIV reservoir is primarily composed of latently infected CD4+ T cells carrying integrated, replication-competent provirus that can give rise to rebound viremia if ART is stopped. Myeloid lineage cells also contribute to HIV latency in certain tissues; we focus here on CD4+ T cells as a sufficient body of evidence regarding latency reversal in myeloid cells is lacking. The immunomodulatory LRA 2.0 approaches we describe include pattern recognition receptor agonists, immune checkpoint inhibitors, non-canonical NF-kB stimulation, and transient CD8+ lymphocyte depletion, along with promising combination strategies. We highlight recent studies demonstrating robust latency reversal in nonhuman primate models.SummaryWhile significant strides have been made in terms of virus reactivation from latency, initial hopes for latency reversal alone to result in a reduction of infected cells, through viral cytopathic effect or an unboosted immune system, have not been realized and it seems clear that even effective latency reversal strategies will need to be paired with an approach that facilitates immune recognition and clearance of cells containing reactivated virus.
Highlights
Purpose of Review For most people living with HIV (PLWH), treatment with effective antiretroviral therapy (ART) results in suppression of viremia below the limit of detection of clinical assays, immune reconstitution, reduced immune activation, avoidance of opportunistic infections, and progression to AIDS
In 2012, it was reported that a single dose of vorinostat administered to 7 participants on suppressive ART induced a significant increase in cell-associated unspliced (CA US) HIV-1 RNA in resting CD4+ T cells [7]
The clinical studies to date show that latency reversal agents (LRA) 1.0 approaches resulted in modest increases in CA US HIV-1 RNA, rare and limited increases in viremia, and no reduction of the viral reservoir in study participants maintained on suppressive ART
Summary
Pattern recognition receptors (PRR) are central players of innate immunity involved in pathogen sensing. The TLR-9 ligand MGN1703 that stimulates type I interferon from pDCs was advanced to clinical trials. An effect on on-ART viremia was not reported in this study and in a similar trial of a different TLR-9 agonist (CpG-ODN7909) [38], presumably if significant increases were seen, these would have been included in the published results. In addition to the well-characterized TLR, cytosolic PRR have been explored as potential targets of the shock approach including retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), and stimulator of interferon genes (STING). An FDA-approved retinoic acid derivative that enhances RIG-I signaling, has been shown to increase HIV transcription in vitro and induce preferential apoptosis of HIVinfected cells [40]. The STING ligands 2′3′-cGAMP and c-dAMP have been reported to increase SIV RNA levels and
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
