The Receptor Tyrosine Kinase RON Represses HIV-1 Transcription by Targeting RNA Polymerase II Processivity

Klatt, Alicia; Zhang, Zhiqiang; Hankey, Pamela A.; Gilmour, David S.; Henderson, Andrew J.

doi:10.4049/jimmunol.180.3.1670

Cited by 20 publications

(27 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…On the other hand, the idea that transcriptional interference would govern latent HIV-1 infection is somewhat in conflict with studies that report that paused RNA polymerase II (RNAP II) is found at the latent HIV-1 promoter (37,38,86). In addition, the involvement of upstream transcriptional control mechanisms in HIV-1 latency is suggested by a series of other studies.…”

mentioning

confidence: 48%

Selected Drugs with Reported Secondary Cell-Differentiating Capacity Prime Latent HIV-1 Infection for Reactivation

Shishido

Wolschendorf

Duverger

et al. 2012

J Virol

View full text Add to dashboard Cite

Reactivation of latent HIV-1 infection is considered our best therapeutic means to eliminate the latent HIV-1 reservoir. Past therapeutic attempts to systemically trigger HIV-1 reactivation using single drugs were unsuccessful. We thus sought to identify drug combinations consisting of one component that would lower the HIV-1 reactivation threshold and a synergistic activator. With aclacinomycin and dactinomycin, we initially identified two FDA-approved drugs that primed latent HIV-1 infection in T cell lines and in primary T cells for reactivation and facilitated complete reactivation at the population level. This effect was correlated not with the reported primary drug effects but with the cell-differentiating capacity of the drugs. We thus tested other cell-differentiating drugs/compounds such as cytarabine and aphidicolin and found that they also primed latent HIV-1 infection for reactivation. This finding extends the therapeutic promise of N ′- N ′-hexamethylene-bisacetamide (HMBA), another cell-differentiating agent that has been reported to trigger HIV-1 reactivation, into the group of FDA-approved drugs. To this end, it is also noteworthy that suberoylanilide hydroxamic acid (SAHA), a polar compound that was initially developed as a second-generation cell-differentiating agent using HMBA as a structural template and which is now marketed as the histone deacetylase (HDAC) inhibitor vorinostat, also has been reported to trigger HIV-1 reactivation. Our findings suggest that drugs with primary or secondary cell-differentiating capacity should be revisited as HIV-1-reactivating agents as some could potentially be repositioned as candidate drugs to be included in an induction therapy to trigger HIV-1 reactivation.

show abstract

mentioning

confidence: 48%

Selected Drugs with Reported Secondary Cell-Differentiating Capacity Prime Latent HIV-1 Infection for Reactivation

Shishido

Wolschendorf

Duverger

et al. 2012

J Virol

View full text Add to dashboard Cite

show abstract

“…39 In humans, the overexpression of RON in monocytes and macrophages decreases the binding activity of NF-B and RNA polymerase II to the long terminal repeats of human immunodeficiency virus and inhibits proviral transcription. 40 In EBV-associated diseases, Renne et al demonstrated that 6 PTKs, including RON, are expressed in Hodgkin/Reed-Sternberg cells of Hodgkin lymphoma and suggested that RON may be involved in the pathogenesis of Hodgkin lymphoma. 41 Our results …”

Section: Discussionmentioning

confidence: 99%

Requirement for LMP1-induced RON receptor tyrosine kinase in Epstein-Barr virus–mediated B-cell proliferation

Chou

Lin

et al. 2011

Blood

View full text Add to dashboard Cite

IntroductionPrimary EBV infection usually is asymptomatic but persists, so that more than 90% of adults worldwide are persistently infected with EBV. 1 However, as the first human tumor virus identified, EBV is associated with several disorders of lymphocytes, including infectious mononucleosis, Burkitt lymphoma, Hodgkin lymphoma, T-cell lymphoma, NK-cell lymphoma, AIDS-associated lymphoma, and posttransplantation lymphoproliferative disorder (PTLD). 1 Being an oncogenic virus, EBV can immortalize primary B cells into lymphoblastoid cell lines (LCLs). EBV-immortalized LCLs are characterized by several features, including aberrant production of cytokines and chemokines, unlimited proliferation, clumping morphology, and display of an EBV latency III phenotype, characteristics similar to those of PTLD. 2 Indeed, LCLs are good in vitro models to understand the pathogenesis of, and to discover novel therapeutic targets for, PTLD.EBV encodes several proteins which mimic or associate with host cellular factors and these factors are well documented in B-cell survival, differentiation, proliferation, and immortalization. 1 (1) The latent membrane protein 1 (LMP1) acts as a constitutively activated CD40 receptor, which provides signals of survival and differentiation in B cells. In LMP1 transgenic mice, constitutively activated LMP1 drives B-cell lymphoma formation, suggesting that LMP1 acts as an oncogene and plays an important role in EBV-mediated tumorigenesis. 1,3 (2) The latent membrane protein 2A (LMP2A) mimics a functional B-cell receptor (BCR). It interacts with Syk and Lyn tyrosine kinases to deliver survival signals through PKC and intracellular calcium. In LMP2A transgenic mice, LMP2A can rescue BCR-lacking B cells from apoptosis, suggesting that the BCR-driven survival signals can be replaced by LMP2A. 4 (3) The Epstein-Barr nuclear antigen 2 (EBNA2) mimics Notch signaling. It interacts with the DNAbinding protein RBPJ/CBP to interfere with Notch-mediated inhibition of B-cell proliferation and differentiation. 1 (4) Zta, a transactivator, mimics a functional and structural AP-1 protein. It plays an important role in regulating cytokine expression by immune cells, such as IL-13. 5 (5) BCRF-1, which is an IL-10 homologue, serves as a growth factor for B cells and suppresses antiviral immune responses. 6 So, we wondered whether any other specific cellular genes are involved in EBV-mediated immortalization. In this study, tyrosine kinases are our target.Among the proteins encoded by the huge human genome, about ninety protein tyrosine kinases (PTKs) have been defined. 7 PTKs are tightly regulated in cells because they play vital roles in crucial biologic functions, such as survival, proliferation, differentiation, and development. 8 Dysregulation of PTK activity is one of the most common mechanisms leading to cellular transformation and cancer formation. 7 Of note, the discovery of PTKs stemmed from the study of an oncogenic virus, Rous sarcoma virus encoding v-src. 9 Generally, viruses can activate PTKs to transf...

show abstract

“…No direct experimental evidence for this hypothesis has been provided, but restriction of P-TEFb and TFIIH, two important components of the actively transcribing RNA polymerase II complex, has been shown to contribute to a latent phenotype (11,12). To this end, paused RNA polymerase II complex has been found associated with the latent LTR promoter (11,(26)(27)(28)(29).…”

mentioning

confidence: 99%

An AP-1 Binding Site in the Enhancer/Core Element of the HIV-1 Promoter Controls the Ability of HIV-1 To Establish Latent Infection

Duverger

Wolschendorf

Zhang

et al. 2013

J Virol

106

View full text Add to dashboard Cite

cFollowing integration, HIV-1 in most cases produces active infection events; however, in some rare instances, latent infection events are established. The latter have major clinical implications, as latent infection allows the virus to persist despite antiretroviral therapy. Both the cellular factors and the viral elements that potentially determine whether HIV-1 establishes active or latent infection events remain largely elusive. We detail here the contribution of different long terminal repeat (LTR) sequences for the establishment of latent HIV-1 infection. Using a panel of full-length replication-competent virus constructs that reflect naturally occurring differences of HIV-1 subtype-specific LTRs and targeted LTR mutants, we found the primary ability of HIV-1 to establish latent infection in this system to be controlled by a four-nucleotide (nt) AP-1 element just upstream of the NF-B element in the viral promoter. Deletion of this AP-1 site mostly deprived HIV-1 of the ability to establish latent HIV-1 infection. Extension of this site to a 7-nt AP-1 sequence massively promoted latency establishment, suggesting that this promoter region represents a latency establishment element (LEE). Given that these minimal changes in a transcription factor binding site affect latency establishment to such large extent, our data support the notion that HIV-1 latency is a transcription factor restriction phenomenon.

show abstract

The Receptor Tyrosine Kinase RON Represses HIV-1 Transcription by Targeting RNA Polymerase II Processivity

Cited by 20 publications

References 67 publications

Selected Drugs with Reported Secondary Cell-Differentiating Capacity Prime Latent HIV-1 Infection for Reactivation

Selected Drugs with Reported Secondary Cell-Differentiating Capacity Prime Latent HIV-1 Infection for Reactivation

Requirement for LMP1-induced RON receptor tyrosine kinase in Epstein-Barr virus–mediated B-cell proliferation

An AP-1 Binding Site in the Enhancer/Core Element of the HIV-1 Promoter Controls the Ability of HIV-1 To Establish Latent Infection

Contact Info

Product

Resources

About