EPHA2 sequence variants are associated with susceptibility to Kaposi’s sarcoma-associated herpesvirus infection and Kaposi’s sarcoma prevalence in HIV-infected patients

Blumenthal, Melissa J.; Schutz, Charlotte; Meintjes, Graeme; Mohamed, Zainab; Mendelson, Marc; Ambler, Jon; Whitby, Denise; Mackelprang, Romel D.; Carse, Sinead; Katz, Arieh A.; Schäfer, Georgia

doi:10.1016/j.canep.2018.08.005

Cited by 18 publications

(27 citation statements)

References 45 publications

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“…Further, our results demonstrate that an RRV gL-null mutant can still elicit potent immune responses to a vectored antigen. In the light of recent findings that show an association between variants in the gene coding for the human EphA2 KSHV receptor and KSHV infection as well as development of Kaposi's sarcoma (42), our findings with an Eph-detargeted rhadinovirus mutant successfully vectoring an SIV antigen may have implications for the development of a live-attenuated KSHV vaccine or the use of live-attenuated KSHV as a vaccine vector.…”

Section: Discussionmentioning

confidence: 56%

A Recombinant Rhesus Monkey Rhadinovirus Deleted of Glycoprotein L Establishes Persistent Infection of Rhesus Macaques and Elicits Conventional T Cell Responses

Hahn

Bischof

Großkopf

et al. 2020

J Virol

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A replication-competent, recombinant strain of rhesus monkey rhadinovirus (RRV) expressing the Gag protein of SIVmac239 was constructed in the context of a glycoprotein L (gL) deletion mutation. Deletion of gL detargets the virus from Eph family receptors. The ability of this gL-minus Gag recombinant RRV to infect, persist, and elicit immune responses was evaluated after intravenous inoculation of two Mamu-A*01+ RRV-naive rhesus monkeys. Both monkeys responded with an anti-RRV antibody response, and quantitation of RRV DNA in peripheral blood mononuclear cells (PBMC) by real-time PCR revealed levels similar to those in monkeys infected with recombinant gL+ RRV. Comparison of RRV DNA levels in sorted CD3+ versus CD20+ versus CD14+ PBMC subpopulations indicated infection of the CD20+ subpopulation by the gL-minus RRV. This contrasts with results obtained with transformed B cell lines in vitro, in which deletion of gL resulted in markedly reduced infectivity. Over a period of 20 weeks, Gag-specific CD8+ T cell responses were documented by major histocompatibility complex class I (MHC-I) tetramer staining. Vaccine-induced CD8+ T cell responses, which were predominantly directed against the Mamu-A*01-restricted Gag181-189CM9 epitope, could be inhibited by blockade of MHC-I presentation. Our results indicate that gL and the interaction with Eph family receptors are dispensable for the colonization of the B cell compartment following high-dose infection by the intravenous route, which suggests the existence of alternative receptors. Further, gL-minus RRV elicits cellular immune responses that are predominantly canonical in nature. IMPORTANCE Kaposi’s sarcoma-associated herpesvirus (KSHV) is associated with a substantial disease burden in sub-Saharan Africa, often in the context of human immunodeficiency virus (HIV) infection. The related rhesus monkey rhadinovirus (RRV) has shown potential as a vector to immunize monkeys with antigens from simian immunodeficiency virus (SIV), the macaque model for HIV. KSHV and RRV engage cellular receptors from the Eph family via the viral gH/gL glycoprotein complex. We have now generated a recombinant RRV that expresses the SIV Gag antigen and does not express gL. This recombinant RRV was infectious by the intravenous route, established persistent infection in the B cell compartment, and elicited strong immune responses to the SIV Gag antigen. These results argue against a role for gL and Eph family receptors in B cell infection by RRV in vivo and have implications for the development of a live-attenuated KSHV vaccine or vaccine vector.

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Section: Discussionmentioning

confidence: 56%

A Recombinant Rhesus Monkey Rhadinovirus Deleted of Glycoprotein L Establishes Persistent Infection of Rhesus Macaques and Elicits Conventional T Cell Responses

Hahn

Bischof

Großkopf

et al. 2020

J Virol

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“…While EphA2 has been well characterised in the oncogenesis of breast cancer, its association with lesser prevalent cancers such as KS is still being elucidated. So far, EphA2 sequence variations in KS patients have been identified and their functional significance investigated, but the consequences for KS oncogenesis are not yet fully understood [ 82 ]. Therefore, subsequent research into EphA2’s role in KS development is required, which will potentially also shed light on the oncogenic role of EphA2 in other cancers.…”

Section: Discussionmentioning

confidence: 99%

“…This suggests that the processes of KSHV infection and KS progression may also have host genetic components to them. Previous work from our laboratory found that EphA2 sequence variants were associated both with KSHV infection and KS prevalence in HIV-infected patients [ 82 ]. These variants were identified in the intracellular and functionally important Pkinase-Tyr and SAM domains.…”

Section: Epha2 Plays a Dual Role In Kaposi’s Sarcoma Oncogenesismentioning

confidence: 99%

“…While Pkinase-Tyr variations were associated with KS may be due to enhanced EphA2 Pkinase-Tyr signalling, variations associated with susceptibility to KSHV infection were hypothesised to be related to an enhancement in the EphA2 signalling downstream of KSHV binding necessary for its internalisation. Altered SAM functioning is likely behind the association between variations in the SAM domain and KS because of this region’s role in mediating signalling downstream of EphA2 activation through the binding of adaptor proteins [ 82 ].…”

Section: Epha2 Plays a Dual Role In Kaposi’s Sarcoma Oncogenesismentioning

confidence: 99%

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The Role of the Eph Receptor Family in Tumorigenesis

Anderton

Meulen

Blumenthal

et al. 2021

Cancers

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The Eph receptor tyrosine kinase family, activated by binding to their cognate ephrin ligands, are important components of signalling pathways involved in animal development. More recently, they have received significant interest due to their involvement in oncogenesis. In most cases, their expression is altered, affecting the likes of cell proliferation and migration. Depending on the context, Eph receptors have the potential to act as both tumour promoters and suppressors in a number of cancers, such as breast cancer, colorectal cancer, lung cancer, prostate cancer, brain cancer and Kaposi’s sarcoma (KS), the latter being intrinsically linked to EphA2 as this is the receptor used for endothelial cell entry by the Kaposi’s sarcoma-associated herpesvirus (KSHV). In addition, EphA2 deregulation is associated with KS, indicating that it has a dual role in this case. Associations between EphA2 sequence variation and KSHV infection/KS progression have been detected, but further work is required to formally establish the links between EphA2 signalling and KS oncogenesis. This review consolidates the available literature of the role of the Eph receptor family, and particularly EphA2, in tumorigenesis, with the aim to develop a better understanding of Eph signalling pathways for potential targeting in novel cancer therapies.

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“…It was further revealed that many amino acids of EPHA2′s LBD are potentially recognized by other γ-herpesviruses, thereby providing the structural basis of EPHA2 recognition by γ-herpesvirus gHgL [ 78 ]. Recently, an investigation of EPHA2 sequence variants in the protein coding region of the gene in South African HIV positive individuals revealed that certain variants, primarily located in the functionally important tyrosine kinase domain, affected patient’s susceptibility to KSHV infection or KS development [ 79 ]. This further supports the current understanding that EPHA2 plays an important role in KSHV entry and may be involved in signaling events leading to KS development.…”

Section: Cell-type Specific Expression Of Surface Receptors Used Bmentioning

confidence: 99%

Cellular Receptors Involved in KSHV Infection

Meulen

Anderton

Blumenthal

et al. 2021

Viruses

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The process of Kaposi’s Sarcoma Herpes Virus’ (KSHV) entry into target cells is complex and engages several viral glycoproteins which bind to a large range of host cell surface molecules. Receptors for KSHV include heparan sulphate proteoglycans (HSPGs), several integrins and Eph receptors, cystine/glutamate antiporter (xCT) and Dendritic Cell-Specific Intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN). This diverse range of potential binding and entry sites allows KSHV to have a broad cell tropism, and entry into specific cells is dependent on the available receptor repertoire. Several molecules involved in KSHV entry have been well characterized, particularly those postulated to be associated with KSHV-associated pathologies such as Kaposi’s Sarcoma (KS). In this review, KSHV infection of specific cell types pertinent to its pathogenesis will be comprehensively summarized with a focus on the specific cell surface binding and entry receptors KSHV exploits to gain access to a variety of cell types. Gaps in the current literature regarding understanding interactions between KSHV glycoproteins and cellular receptors in virus infection are identified which will lead to the development of virus infection intervention strategies.

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EPHA2 sequence variants are associated with susceptibility to Kaposi’s sarcoma-associated herpesvirus infection and Kaposi’s sarcoma prevalence in HIV-infected patients

Abstract: Variations in the KSHV entry receptor gene EPHA2 affected susceptibility to KSHV infection and KS development in a South African HIV-infected patient cohort.

Cited by 18 publications

References 45 publications

A Recombinant Rhesus Monkey Rhadinovirus Deleted of Glycoprotein L Establishes Persistent Infection of Rhesus Macaques and Elicits Conventional T Cell Responses

A Recombinant Rhesus Monkey Rhadinovirus Deleted of Glycoprotein L Establishes Persistent Infection of Rhesus Macaques and Elicits Conventional T Cell Responses

The Role of the Eph Receptor Family in Tumorigenesis

Cellular Receptors Involved in KSHV Infection

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