Abstract:Human cytomegalovirus (HCMV) is implicated in the acceleration of a number of vascular diseases including transplant vascular sclerosis (TVS), the lesion associated with chronic rejection (CR) of solid organ transplants. Although the virus persists in the allograft throughout the course of disease, few cells are directly infected by CMV. This observation is in contrast to the global effects that CMV has on the acceleration of TVS/CR, suggesting that CMV infection indirectly promotes the vascular disease proces… Show more
“…Consequently, IE84-mediated inhibition of p53 function may enhance proliferation of SMCs and contribute to coronary restenosis (129). HCMV-infected fibroblasts and ECs secrete PDGF, a mitogen and chemoattractant for mesenchymal cells, and TGF-b, which may produce changes in myofibroblasts and pericytes to promote stabilization of new vessels (120,133). Because SMC migration into the neointimal space is the hallmark of vascular disease, these observations provide a molecular link between HCMV and graft arterial vascular disease (134).…”
Section: Colony-stimulating Factor) Hcmv Infection Of Ecs Induces Exmentioning
confidence: 99%
“…This includes laminins and >41 cytokines, chemokines and chemokine receptors that affect angiogenesis and wound healing (chemokines IL-6, osteoprotegerin, growth-regulated oncogene, C-C motif chemokine ligand [CCL] 3, CCL5, CCL7, CCL20, CXCL5, and CXCL16; receptors TNF receptors I and II and ICAM1; growth factors TGF-b1, hepatocyte growth factor and granulocyte macrophage (122) and VCAM1, which, in the early phase of infection, enhance transendothelial cell migration of inflammatory cells including monocytes, promoting angiogenesis by secretion of VEGF (120,123). Vascular proliferation is facilitated by degradation of basal membranes by matrix metalloproteinases and tissue inhibitors of matrix metalloproteinase released by HCMV-infected fibroblast and epithelial cells (120).…”
Section: Proangiogenic and Proliferative Effectsmentioning
Interpretation of clinical data regarding the impact of cytomegalovirus (CMV) infection on allograft function is complicated by the diversity of viral strains and substantial variability of cellular receptors and viral gene expression in different tissues. Variation also exists in nonspecific (monocytes and dendritic cells) and specific (NK cells, antibodies) responses that augment T cell antiviral activities. Innate immune signaling pathways and expanded pools of memory NK cells and cd T cells also serve to amplify host responses to infection. The clinical impact of specific memory T cell anti-CMV responses that cross-react with graft antigens and alloantigens is uncertain but appears to contribute to graft injury and to the abrogation of allograft tolerance. These responses are modified by diverse immunosuppressive regimens and by underlying host immune deficits. The impact of CMV infection on the transplant recipient reflects cellular changes and corresponding host responses, the convergence of which has been termed the "indirect effects" of CMV infection. Future studies will clarify interactions between CMV infection and allograft injury and will guide interventions that may enhance clinical outcomes in transplantation.
“…Consequently, IE84-mediated inhibition of p53 function may enhance proliferation of SMCs and contribute to coronary restenosis (129). HCMV-infected fibroblasts and ECs secrete PDGF, a mitogen and chemoattractant for mesenchymal cells, and TGF-b, which may produce changes in myofibroblasts and pericytes to promote stabilization of new vessels (120,133). Because SMC migration into the neointimal space is the hallmark of vascular disease, these observations provide a molecular link between HCMV and graft arterial vascular disease (134).…”
Section: Colony-stimulating Factor) Hcmv Infection Of Ecs Induces Exmentioning
confidence: 99%
“…This includes laminins and >41 cytokines, chemokines and chemokine receptors that affect angiogenesis and wound healing (chemokines IL-6, osteoprotegerin, growth-regulated oncogene, C-C motif chemokine ligand [CCL] 3, CCL5, CCL7, CCL20, CXCL5, and CXCL16; receptors TNF receptors I and II and ICAM1; growth factors TGF-b1, hepatocyte growth factor and granulocyte macrophage (122) and VCAM1, which, in the early phase of infection, enhance transendothelial cell migration of inflammatory cells including monocytes, promoting angiogenesis by secretion of VEGF (120,123). Vascular proliferation is facilitated by degradation of basal membranes by matrix metalloproteinases and tissue inhibitors of matrix metalloproteinase released by HCMV-infected fibroblast and epithelial cells (120).…”
Section: Proangiogenic and Proliferative Effectsmentioning
Interpretation of clinical data regarding the impact of cytomegalovirus (CMV) infection on allograft function is complicated by the diversity of viral strains and substantial variability of cellular receptors and viral gene expression in different tissues. Variation also exists in nonspecific (monocytes and dendritic cells) and specific (NK cells, antibodies) responses that augment T cell antiviral activities. Innate immune signaling pathways and expanded pools of memory NK cells and cd T cells also serve to amplify host responses to infection. The clinical impact of specific memory T cell anti-CMV responses that cross-react with graft antigens and alloantigens is uncertain but appears to contribute to graft injury and to the abrogation of allograft tolerance. These responses are modified by diverse immunosuppressive regimens and by underlying host immune deficits. The impact of CMV infection on the transplant recipient reflects cellular changes and corresponding host responses, the convergence of which has been termed the "indirect effects" of CMV infection. Future studies will clarify interactions between CMV infection and allograft injury and will guide interventions that may enhance clinical outcomes in transplantation.
“…69,71,72 Manipulation of the cellular microenvironment by changes in the cell secretome HCMV lytic infection is also known to induce profound alterations in levels of secreted cellular proteins (secretome) and this includes a number of chemokines and cytokines with immune functions. 73,74 However, until recently, little was known about latency-associated changes in the cell secretome. The possibility that viral manipulation of secreted cellular proteins would likely be an effective mechanism to modify the microenvironment around latently infected cells to help maintain life-long carriage of latent virus in the face of constant immune surveillance has been investigated by us and others.…”
Section: Immune Evasion Strategies During Latent Infectionmentioning
While the host immune response following primary human cytomegalovirus (HCMV) infection is generally effective at stopping virus replication and dissemination, virus is never cleared by the host and like all herpesviruses, persists for life. At least in part, this persistence is known to be facilitated by the ability of HCMV to establish latency in myeloid cells in which infection is essentially silent with, importantly, a total lack of new virus production. However, although the viral transcription programme during latency is much suppressed, a number of viral genes are expressed during latent infection at the protein level and many of these have been shown to have profound effects on the latent cell and its environment. Intriguingly, many of these latency-associated genes are also expressed during lytic infection. Therefore, why the same potent host immune responses generated during lytic infection to these viral gene products are not recognized during latency, thereby allowing clearance of latently infected cells, is far from clear. Reactivation from latency is also a major cause of HCMV-mediated disease, particularly in the immune compromised and immune naive, and is also likely to be a major source of virus in chronic subclinical HCMV infection which has been suggested to be associated with long-term diseases such as atherosclerosis and some neoplasias. Consequently, understanding latency and why latently infected cells appear to be immunoprivileged is crucial for an understanding of the pathogenesis of HCMV and may help to design strategies to eliminate latent virus reservoirs, at least in certain clinical settings.
“…HCMV is known to regulate the secretion of numerous cellular chemokines, cytokines, and growth factors during lytic infection (7,8). Little is known, however, about the changes that occur in the secretome during latent infection, and yet this is likely to be of great importance for carriage of latently infected cells in vivo.…”
After primary infection, human cytomegalovirus (HCMV) persists as a life-long latent infection, with host immunosuppression often resulting in clinical reactivation. During lytic infection, major changes in the expression of secreted cellular proteins (the secretome) occur that have profound effects on host–cell interactions, particularly at the level of the host immune response. In contrast, little is known about changes in the secretome that accompany latent infection, yet this is likely to be of major importance for the life-long carriage of this persistent human pathogen in the face of constant immunosurveillance. We have analyzed the secretome of cells carrying latent HCMV and have identified changes in several secreted cellular proteins known to be involved in regulation of the immune response and chemoattraction. Here, we show that a latency-associated increase in CC chemokine ligand (CCL)8 results in the recruitment of cluster of differentiation (CD)4
+
T cells to supernatants from latently infected CD34
+
cells but that these latent supernatants, also rich in immunosuppressive factors, inhibit cytokine secretion and cytotoxicity of HCMV-specific T-helper (Th)1 CD4
+
T cells. These results identify a strategy by which sites of latent HCMV can firstly recruit CD4
+
T cells and then inhibit their antiviral effector functions, thereby aiding the maintenance of latent infection in the face of the host immune response.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.