HIV-1 matrix protein p17 promotes angiogenesis via chemokine receptors CXCR1 and CXCR2

Abstract

Vascular diseases supported by aberrant angiogenesis have increased incidence in HIV-1-infected patients. Several data suggest that endothelium dysfunction relies on action of HIV-1 proteins rather than on a direct effect of the virus itself. The HIV-1 matrix protein p17 is known to deregulate the biological activity of different immune cells. Recently, p17 was found to mimic IL-8 chemokine activity by binding to the IL-8 receptor CXCR1. Here we show that p17 binds with high affinity to CXCR2, a CXCR1-related receptor, and promotes the formation of capillary-like structures on human endothelial cells (ECs) by interacting with both CXCR1 and CXCR2 expressed on the EC surface. ERK signaling via Akt was defined as the pathway responsible for p17-induced tube formation. Ex vivo and in vivo experimental models confirmed the provasculogenic activity of p17, which was comparable to that induced by VEGF-A. The hypothesis of a major role for p17 in HIV-1-induced aberrant angiogenesis is enforced by the finding that p17 is detected, as a single protein, in blood vessels of HIV-1-patients and in particular in the nucleus of ECs. Localization of p17 in the nucleus of ECs was evidenced also in in vitro experiments, suggesting the internalization of exogenous p17 in ECs by mechanisms of receptormediated endocytosis. Recognizing p17 interaction with CXCR1 and CXCR2 as the key event in sustaining EC aberrant angiogenesis could help us to identify new treatment strategies in combating AIDSrelated vascular diseases. extracellular viral proteins | virokine | Akt-mediated ERK pathway | vasculogenic assays | surface plasmon resonance A ngiogenesis is a physiological process requiring growth of new blood vessels from preexisting vessels. This process involves coordinated endothelial cell (EC) proliferation, invasion, migration, and tube formation (1). When new vessels are required, proangiogenic factors are produced, whereas restoration of physiological conditions is achieved by producing inhibitors of angiogenesis and vessel stabilization factors. Breakdown of the tight regulated angiogenic balance leads to dysfunctional endothelium, abnormal angiogenesis, and vascular diseases.

Role of HIV-1 matrix protein p17 variants in lymphoma pathogenesis

“…Recent data have highlighted the capability of p17 to also promote both angiogenesis (25,26) and lymphangiogenesis (26,27), which are essential in supporting proliferation and survival of lymphoma, as well as tumor cell dissemination (28). Altogether, these evidences corroborate the hypothesis that p17 may play a key role in producing a microenvironment that fosters lymphoma development, progression, and metastasis.…”

Molecular Interaction Studies of HIV-1 Matrix Protein p17 and Heparin

“…Extracellular p17 deregulates the functions of many immune cells involved in AIDS pathogenesis (7): it reduces MIP-1␣ secretion in activated monocytes (8), induces activated T cell proliferation enhancing HIV replication (9), increases IFN-␥ and TNF-␣ production decreasing the ability of IL-4 to down-regulate the secretion of such cytokines in activated peripheral blood mononuclear and natural killer cells (7,10). Three distinct cellular receptors for p17 have been identified: the chemokine receptors CXCR1 and CXCR2, which mediate p17-driven monocyte migration (11) and endothelial cells proangiogenic activation (12), respectively, and heparan sulfate proteoglycans (HSPGs), 2 tentatively associated to p17-driven cytokine up-regulation in CD4ϩ lymphocytes (13,14).…”

“…Tat/heparin interaction occurs with a dissociation constant (K d ) equal to 30 -60 nM (20, 21) and is mainly mediated by a linear basic motif 49 RKKRRQRRR 57 located at the C terminus of the protein (22), with a minor contribution of three other basic amino acids (Lys 12 , Lys 41 , and Arg 78 ) spatially enclosed in the native protein (23). At least some 2-O-, 6-O-, and N-positions along the GAG chain need to be sulfated to allow Tat binding (24), and a hexasaccharide is the minimal heparin length that retains Tat-binding capacity (25).…”

Expression of HIV-1 matrix protein p17 and association with B-cell lymphoma in HIV-1 transgenic mice

“…Matrix p17 may influence tumor development at one or more stages, including early B-cell development in BM, B-cell growth in the periphery, and/or support angiogenesis/lymphangiogenesis (18)(19)(20)(21)(22). Although we cannot completely exclude the role of other viral proteins, we did not detect gp120 or Nef in lymph nodes in early disease stages.…”

“…Moreover, proviral sequences for variant p17s that display B-cell growth-promoting activity can be found in HIV-NHL tissues, suggesting a role for variant p17s in lymphoma pathogenesis (12). In addition to its effects on B cells, p17 can induce angiogenesis/lymphangiogenesis in vitro and in vivo (20)(21)(22). In addition, cumulative viremia during cART is known to be a strong predictor of HIV-NHL, especially for BL (23).…”