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Promising role of toll-like receptor 8 agonist in concert with prostratin for activation of silent HIV


Rochat, M A; Schlaepfer, E; Speck, R F (2017). Promising role of toll-like receptor 8 agonist in concert with prostratin for activation of silent HIV. Journal of Virology, 91(4):e02084-16.

Abstract

The persistence of latently HIV-infected cells in patients under combined anti-retroviral treatment (cART) remains the major hurdle for HIV eradication. Thus far, individual compounds have not been sufficiently potent to reactivate latent virus and guarantee its elimination in vivo Thus, we hypothesized that transcriptional enhancers, in concert with compounds triggering the innate immune system, are more efficient in reversing latency by creating a Th1 supportive milieu that acts against latently HIV-infected cells at various levels. To test our hypothesis, we screened six compounds on a co-culture of latently infected cells (J-lat) and monocyte-derived dendritic cells (MDDCs). The PKC agonist, Prostratin, with a TLR8 agonist, resulted in greater reversion of HIV latency than any single compound. This combinatorial approach led to a drastic phenotypic and functional maturation of the MDDCs. TNF and cell-cell interactions were crucial for the greater reversion observed. Similarly, we found a greater potency of the combination of Prostratin/TLR8 agonist in reversing HIV latency when applying it to primary cells of HIV-infected patients. Thus, we demonstrated here the synergistic interplay between TLR8-matured MDDCs and compounds acting directly on latently HIV-infected cells, targeting different mechanisms of latency, by triggering various signaling pathways. Moreover, TLR8 triggering may reverse exhaustion of HIV-specific cytotoxic T lymphocytes that might be essential for killing or constraining the latently infected cells.
IMPORTANCE Curing HIV is the Holy Grail. The so-called "shock and kill strategy" relies on drug-mediated reversion of HIV latency and the subsequent death of those cells under combined anti-retroviral treatment. So far, no compound achieves efficient reversal of latency nor eliminates this latent reservoir. The compounds may not target all of the latency mechanisms in all latently infected cells. Moreover, HIV-associated exhaustion of the immune system hinders the efficient elimination of the reactivated cells. In this study, we demonstrated synergistic latency reversion by combining agonists for protein kinase C and toll-like receptor 8 in a co-culture of latently infected cells with myeloid dendritic cells. The drug Prostratin stimulates directly the transcriptional machinery of latently infected cells and the TLR8 agonist acts indirectly by maturing dendritic cells. These findings highlight the importance of the immune system and its activation, in combination with direct acting compounds, to reverse latency.

Abstract

The persistence of latently HIV-infected cells in patients under combined anti-retroviral treatment (cART) remains the major hurdle for HIV eradication. Thus far, individual compounds have not been sufficiently potent to reactivate latent virus and guarantee its elimination in vivo Thus, we hypothesized that transcriptional enhancers, in concert with compounds triggering the innate immune system, are more efficient in reversing latency by creating a Th1 supportive milieu that acts against latently HIV-infected cells at various levels. To test our hypothesis, we screened six compounds on a co-culture of latently infected cells (J-lat) and monocyte-derived dendritic cells (MDDCs). The PKC agonist, Prostratin, with a TLR8 agonist, resulted in greater reversion of HIV latency than any single compound. This combinatorial approach led to a drastic phenotypic and functional maturation of the MDDCs. TNF and cell-cell interactions were crucial for the greater reversion observed. Similarly, we found a greater potency of the combination of Prostratin/TLR8 agonist in reversing HIV latency when applying it to primary cells of HIV-infected patients. Thus, we demonstrated here the synergistic interplay between TLR8-matured MDDCs and compounds acting directly on latently HIV-infected cells, targeting different mechanisms of latency, by triggering various signaling pathways. Moreover, TLR8 triggering may reverse exhaustion of HIV-specific cytotoxic T lymphocytes that might be essential for killing or constraining the latently infected cells.
IMPORTANCE Curing HIV is the Holy Grail. The so-called "shock and kill strategy" relies on drug-mediated reversion of HIV latency and the subsequent death of those cells under combined anti-retroviral treatment. So far, no compound achieves efficient reversal of latency nor eliminates this latent reservoir. The compounds may not target all of the latency mechanisms in all latently infected cells. Moreover, HIV-associated exhaustion of the immune system hinders the efficient elimination of the reactivated cells. In this study, we demonstrated synergistic latency reversion by combining agonists for protein kinase C and toll-like receptor 8 in a co-culture of latently infected cells with myeloid dendritic cells. The drug Prostratin stimulates directly the transcriptional machinery of latently infected cells and the TLR8 agonist acts indirectly by maturing dendritic cells. These findings highlight the importance of the immune system and its activation, in combination with direct acting compounds, to reverse latency.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Infectious Diseases
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:2017
Deposited On:26 Jan 2017 10:19
Last Modified:04 Aug 2017 19:22
Publisher:American Society for Microbiology
ISSN:0022-538X
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1128/JVI.02084-16
PubMed ID:27928016

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