Synergistic reactivation of latent HIV-1 provirus by PKA activator dibutyryl-cAMP in combination with an HDAC inhibitor

Lim, Hye‐Sun; Kim, Kyung-Chang; Son, Junseock; Shin, YoungHyun; Yoon, Choon Sik; Kang, Chun; Choi, Byeong‐Sun

doi:10.1016/j.virusres.2016.09.015

Cited by 15 publications

(17 citation statements)

References 27 publications

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“…Because our phosphoproteomic analysis identified PKA, also known as cAMP-dependent protein kinase, as a novel kinase active during BTV infection, we wanted to validate and assess its role during BTV replication. To this end, we used the PKA inhibitor H89 ( 34 ) and the PKA activator Dibutyryl-cAMP ( 35 ) to explore the effects of PKA inhibition and activation on BTV replication. Although HeLa cells support BTV replication successfully and were chosen for the initial phosphoproteomic characterization of BTV infection, because of the superior annotation of the human proteome and availability of analysis tools ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Phosphoproteomic Analysis Reveals the Importance of Kinase Regulation During Orbivirus Infection

Mohl

Emmott

Roy

2017

Molecular & Cellular Proteomics

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Bluetongue virus (BTV) causes infections in wild and domesticated ruminants with high morbidity and mortality and is responsible for significant economic losses in both developing and developed countries. BTV serves as a model for the study of other members of the Orbivirus genus. Previously, the importance of casein kinase 2 for BTV replication was demonstrated. To identify intracellular signaling pathways and novel host-cell kinases involved during BTV infection, the phosphoproteome of BTV infected cells was analyzed. Over 1000 phosphosites were identified using mass spectrometry, which were then used to determine the corresponding kinases involved during BTV infection. This analysis yielded protein kinase A (PKA) as a novel kinase activated during BTV infection. Subsequently, the importance of PKA for BTV infection was validated using a PKA inhibitor and activator. Our data confirmed that PKA was essential for efficient viral growth. Further, we showed that PKA is also required for infection of equid cells by African horse sickness virus, another member of the Orbivirus genus. Thus, despite their preference in specific host species, orbiviruses may utilize the same host signaling pathways during their replication.

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Section: Resultsmentioning

confidence: 99%

Phosphoproteomic Analysis Reveals the Importance of Kinase Regulation During Orbivirus Infection

Mohl

Emmott

Roy

2017

Molecular & Cellular Proteomics

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“…Finally, we note that additional latency reversal mechanisms by these agents may remain undetected. For example, we previously described alotaketal C as an LRA of the PKC activator class [ 14 ], but it is additionally reported to function as an activator of cyclic AMP signaling [ 20 ], which may also modulate HIV-1 latency reversal [ 40 , 41 ].…”

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confidence: 99%

Identification of Novel HIV-1 Latency-Reversing Agents from a Library of Marine Natural Products

Richard

Williams

Silva

et al. 2018

Viruses

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Natural products originating from marine and plant materials are a rich source of chemical diversity and unique antimicrobials. Using an established in vitro model of HIV-1 latency, we screened 257 pure compounds from a marine natural product library and identified 4 (psammaplin A, aplysiatoxin, debromoaplysiatoxin, and previously-described alotaketal C) that induced expression of latent HIV-1 provirus in both cell line and primary cell models. Notably, aplysiatoxin induced similar levels of HIV-1 expression as prostratin but at up to 900-fold lower concentrations and without substantial effects on cell viability. Psammaplin A enhanced HIV-1 expression synergistically when treated in combination with the protein kinase C (PKC) activator prostratin, but not the histone deacetylase inhibitor (HDACi) panobinostat, suggesting that psammaplin A functions as a latency-reversing agent (LRA) of the HDACi class. Conversely, aplysiatoxin and debromoaplysiatoxin synergized with panobinostat but not prostratin, suggesting that they function as PKC activators. Our study identifies new compounds from previously untested marine natural products and adds to the repertoire of LRAs that can inform therapeutic “shock-and-kill”-based strategies to eliminate latent HIV-infected reservoirs.

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“…However, studies have also questioned their efficacy in HIV-1 reservoirs in vivo 35 , 36 . Therefore, recent publications have underscored the need for using different combinations of LRAs to enable potent latency-reactivation 37 , 38 . We investigated whether coexposure to the ASC-CM can increase the LRA efficacy of vorinostat (SAHA) and panobinostat (Pano) (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, factors secreted by MSCs, or specific signaling pathways activated by primary human MSCs, may provide novel and superior strategies to activate the latent tissue reservoirs, and will no doubt be of more physiologic significance 33 , 38 , 52 . In this respect, several laboratories have shown that the combination of LRAs with different mechanisms of action may be more effective and less toxic in vivo 37 , 38 , 53 . Coexposure to bryostatin (a PKC-agonist) and panobinostat (a HDACi) provided better latency reactivation, as compared to each of these agents alone 53 .…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal stem cells are attracted to latent HIV-1-infected cells and enable virus reactivation via a non-canonical PI3K-NFκB signaling pathway

Chandra

Gerlach

et al. 2018

Sci Rep

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Persistence of latent HIV-1 in macrophages (MACs) and T-helper lymphocytes (THLs) remain a major therapeutic challenge. Currently available latency reversing agents (LRAs) are not very effective in vivo. Therefore, understanding of physiologic mechanisms that dictate HIV-1 latency/reactivation in reservoirs is clearly needed. Mesenchymal stromal/stem cells (MSCs) regulate the function of immune cells; however, their role in regulating virus production from latently-infected MACs & THLs is not known. We documented that exposure to MSCs or their conditioned media (MSC-CM) rapidly increased HIV-1 p24 production from the latently-infected U1 (MAC) & ACH2 (THL) cell lines. Exposure to MSCs also increased HIV-1 long terminal repeat (LTR) directed gene expression in the MAC and THL reporter lines, U937-VRX and J-Lat (9.2), respectively. MSCs exposed to CM from U1 cells (U1-CM) showed enhanced migratory ability towards latently-infected cells and retained their latency-reactivation potential. Molecular studies showed that MSC-mediated latency-reactivation was dependent upon both the phosphatidyl inositol-3-kinase (PI3K) and nuclear factor-κB (NFκB) signaling pathways. The pre-clinically tested inhibitors of PI3K (PX-866) and NFκB (CDDO-Me) suppressed MSC-mediated HIV-1 reactivation. Furthermore, coexposure to MSC-CM enhanced the latency-reactivation efficacy of the approved LRAs, vorinostat and panobinostat. Our findings on MSC-mediated latency-reactivation may provide novel strategies against persistent HIV-1 reservoirs.

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Synergistic reactivation of latent HIV-1 provirus by PKA activator dibutyryl-cAMP in combination with an HDAC inhibitor

Cited by 15 publications

References 27 publications

Phosphoproteomic Analysis Reveals the Importance of Kinase Regulation During Orbivirus Infection

Phosphoproteomic Analysis Reveals the Importance of Kinase Regulation During Orbivirus Infection

Identification of Novel HIV-1 Latency-Reversing Agents from a Library of Marine Natural Products

Mesenchymal stem cells are attracted to latent HIV-1-infected cells and enable virus reactivation via a non-canonical PI3K-NFκB signaling pathway

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