Abstract
We have previously reported that human herpesvirus 6 (HHV-6) infection of endothelial cells (ECs) induces the loss of angiogenic properties, through the expression of HHV-6 U94, possibly associated to the release of a soluble mediator. It is also known that the soluble isoform of HLA-G exhibits an anti-angiogenic function, important in implantation, transplantation and neoplastic development. In this study, we analyzed the expression of HLA-G in HHV-6 infected ECs, showing that both HHV-6A and HHV-6B infection induce a potent up-modulation of HLA-G, including both membrane and soluble isoforms. Interestingly, HHV-6A and HHV-6B induced different isoforms of HLA-G. The virus-induced increase of HLA-G was likely due to the expression of the U94 viral gene, that by itself was able to reproduce the effect of whole virus. The effect of U94 was mediated by human transcription factor ATF3, that induced HLA-G activation by recognizing a consensus sequence on its promoter. Virus-induced inhibition of ECs angiogenic ability directly correlated to HLA-G expression and release, and the addition of anti-HLA-G antibody restored the angiogenic properties of HHV6-infected ECs. The induction of HLA-G expression in ECs might represent an important mediator of HHV-6 induced effects.
Highlights
Herpesviruses have developed several strategies to ensure their persistence in latently infected cells and to evade host immunity during their active replication[11,12]
Our study demonstrates that infection with both HHV-6A and HHV-6B induces the expression of Human Leukocyte Antigen (HLA)-G in infected endothelial cells (ECs), possibly by induction of ATF3 expression, and this correlates with the inability to originate vascular-like structures in culture
When we looked at protein levels, both HHV-6A and HHV-6B induced the expression of membrane-bound HLA-G1 molecules (Fig. 3A)
Summary
Herpesviruses have developed several strategies to ensure their persistence in latently infected cells and to evade host immunity during their active replication[11,12]. HHV-6 has been shown to down modulate Human Leukocyte Antigen (HLA) class I molecule expression in dendritic cells[13], and to induce a selective suppression of IL-12, affecting the generation of effective cellular immune responses[14]. The soluble form of HLA-G possesses an anti-angiogenic activity, inhibiting human ECs ability to form capillary-like structures in vitro[20]. This function has a relevant importance in physiological and pathological settings where the vascular remodeling has an impact in clinical follow-up, such as embryo implantation, tumors and transplantation. Our study demonstrates that infection with both HHV-6A and HHV-6B induces the expression of HLA-G in infected ECs, possibly by induction of ATF3 expression, and this correlates with the inability to originate vascular-like structures in culture
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