Anti-Human Herpesvirus 8 antibodies affect both insulin and glucose uptake by virus-infected human endothelial cells

Abstract

Introduction: Human Herpesvirus 8 (HHV8) is known to be the cause of the malignant tumour named Kaposi's sarcoma. It is believed to induce an intense modification of cell metabolism in endothelial cells. In this work we analysed the role of anti-HHV8 antibodies in both the insulin and glucose uptake of HHV8-infected primary human endothelial cells (HUVEC). Methodology: Western blotting, immunofluorescence and radiolabelled glucose were employed to assess the pPI3K expression, insulin binding and glucose-uptake by HUVEC cells, respectively. Results: We confirmed that HHV8-infection is able to enhance both insulin binding and glucose-uptake in HHV8-infected primary endothelial cells; in addition, we found that anti-HHV8 specific antibodies are able to further increase both insulin and glucose uptake during the late latent phase of HHV8-infection in vitro. Conclusions: These findings suggest that a specific immune response to HHV8-infection may cooperate in boosting the cell metabolism, further enhancing the already increased insulin binding and glucose-uptake in HHV8-infected cells, which is a peculiar property of several oncogenic viruses.

Human Herpesvirus 8 and Host-Cell Interaction: Long-Lasting Physiological Modifications, Inflammation and Related Chronic Diseases

“…Surprisingly, they also discovered that anti-HHV8 antibodies could selectively induce a further increase in insulin and glucose uptake in the latent HHV8-infection. These authors finally suggested that the immune response to HHV8-infection was able to stimulate cell metabolism by inducing an increased insulin and glucose uptake in virus infected cells, as generally happens in several tumour-viral infections [24]. As a matter of fact, when anti-HHV8 antibodies were added to endothelial cells during HHV8 latent infection, a further increase in pPI3K expression and in insulin and glucose uptake was observed.…”

“…In addition, some sulfonamide drugs have recently been shown to be able to interfere with the binding of LANA to the cellular DNA [23]. It is worth noting that several other DNA (e.g., Adenoviruses and Herpesviruses) and RNA (e.g., Rubella, Dengue virus, Enteroviruses, Hepatitis C virus and HIV) viruses were found to be able to affect the host's metabolism favouring not only the onset of tumours but also some other chronic diseases, namely metabolic syndrome and diabetes [4,[24][25][26][27][28][29].…”

“…It has also been reported that HHV8 together with the activation of both humoral and cellular immunity, as well as the induction of cytokines and reactive oxygen species (ROS), induces persistent metabolic modifications in the infected endothelial cells [60,66,[74][75][76][77][78]. Recently, Angius et al [24] corroborated previous evidence [63,65] and also found that the anti-HHV8 immune response can further enhance the uptake of both glucose and insulin in latently infected endothelial cells, strengthening the hypothesis that anti-HHV8 antibodies provide additional support for virus persistence in the host [24]. The vGPCR and K1 proteins are present in a significant amount in the membranes of infected cells, whereas other proteins are preferentially localized in the cytoplasm and the nucleus.…”

“…Moreover, these proteins are known to activate the PI3K pathway in latently infected BC3 lymphoblastic cells, thus enhancing HHV8 pathogenicity. It is noteworthy that PI3K has been reported to stimulate the membrane glucose transporter GLUT4 [24]. Also, mainly anti-lytic phase antibodies were significantly increased in diabetes type 2 (DMT2) patients, whilst anti-latent phase antibodies were not [24,79].…”

“…It is noteworthy that PI3K has been reported to stimulate the membrane glucose transporter GLUT4 [24]. Also, mainly anti-lytic phase antibodies were significantly increased in diabetes type 2 (DMT2) patients, whilst anti-latent phase antibodies were not [24,79]. The latter authors studied the role of specific anti-HHV8 antibodies in the uptake and metabolism of insulin and glucose by HHV8-infected human endothelial cells.…”