Synergy between Kaposi's sarcoma-associated herpesvirus (KSHV) vIL-6 and HIV-1 Nef protein in promotion of angiogenesis and oncogenesis: role of the AKT signaling pathway

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV) is the cause of Kaposi's sarcoma (KS), which is the most common AIDS-associated malignancy. KS is characterized by neovascularization and spindle cell proliferation. The interaction between HIV-1 and KSHV has a central role in promoting the aggressive manifestations of KS in AIDS patients; however, the pathogenesis underlying AIDS-related KS (AIDS-KS) remains unknown. Herein, we examined the potential of HIV-1 negative factor (Nef) to impact KSHV viral interleukin-6 (vIL-6)-induced angiogenesis and tumorigenesis. In vitro experiments showed that exogenous Nef penetrated vIL-6-expressing endothelial cells. Both internalized and ectopic expression of Nef in endothelial cells and fibroblasts synergized with vIL-6 to promote vascular tube formation and cell proliferation. Using a chicken chorioallantoic membrane (CAM) model, we demonstrated that Nef synergistically promotes vIL-6-induced angiogenesis and tumorigenesis. Animal experiments further showed that Nef facilitates vIL-6-induced angiogenesis and tumor formation in athymic nu/nu mice. Mechanistic studies indicated that Nef synergizes with vIL-6 to enhance angiogenesis and tumorigenesis by activating the AKT pathway in the CAM model, as well as nude mice. LY294002, a specific inhibitor of phosphatidylinositol-3-kinase (PI3K), significantly impaired the ability of Nef to promote vIL-6-induced tumorigenesis in an allograft model of nude mice. Our data provide first-line evidence that Nef may contribute to the pathogenesis underlying AIDS-KS in synergy with vIL-6. These novel findings also suggest that targeting the PI3K/AKT signal may be a potentially effective therapeutic approach in AIDS-KS patients.

KSHV

“…vIL6 expression can also induce growth in mouse hybridoma (Hideshima et al, 2000), PEL (Chatterjee, Osborne, Bestetti, Chang, & Moore, 2002; Jones et al, 1999), BAF (Hu & Nicholas, 2006), and Hep3B hepatoma (Nicholas et al, 1997) cell lines. In endothelial cells, vIL6 expression induces proliferation, tubule formation, and neoangiogenesis (Zhou et al, 2013; Zhu et al, 2013). Additionally, vIL6 can help cells escape interferon (IFN)-induced growth arrest (Chatterjee et al, 2002).…”

HIV-1 Vpr Inhibits Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication by Inducing MicroRNA miR-942-5p and Activating NF-κB Signaling

“…Recently, we and others have demonstrated that Tat can not only trigger KSHV reactivation from latency (21) but also accelerate tumor progression induced by KSHV-encoded oncoproteins, including the viral G protein-coupled receptor (vGPCR), kaposin A, viral interleukin-6 (vIL- 6), and open reading frame (ORF) K1 (22)(23)(24)(25). Moreover, we have found that soluble Nef can be readily internalized by PEL cells and endothelial cells, and both soluble and ectopic expressions of Nef promote KSHV latency by inhibiting viral replication and induce angiogenesis and oncogenesis by cooperating with KSHV vIL-6 or ORF K1 (26)(27)(28).…”

Opposing Effects of NGF and proNGF on HIV Induced Macrophage Activation

“…Much of the work done on angiogenesis has been in the context of Kaposi sarcoma, an angioproliferative mesenchymal cancer often seen in AIDS and other immune deficient patients. HIV Tat and nef have been shown to promote Kaposi sarcoma induced angiogenesis (Zhou et al 2013(Zhou et al , 2014. The anti-angiogenic factor thrombospondin-1 inhibits HIV-Kaposi sarcoma induced angiogenic activity (Taraboletti et al 1999).…”