Abstract: CYTOMEGALOVIRUS (CMV) AND THE HUMAN TUMOR CELL SHARE THE SAME OBJECTIVES: escape the recognition and destruction by the immune system and establish a state of immune tolerance conducive for their development. For early tumor development, the escape of the first lines of defense of the immune surveillance is a critical step which determines survival or destruction. The presence of CMV on the tumor site and its involvement in carcinogenesis as initiator or promoter is increasingly documented. In this article, we highlight the similarity between mechanisms used by tumors and CMV to circumvent the immune defenses and evade from immune surveillance. We suggest that CMV and tumors help one another for their common objective. CMV gets shelter in immunologically poor environment of the tumor cells. In return CMV, by acting directly on the cancer cell and/or on the tumor microenvironment, provides the tumor cell the ways to promote its immune escape and development of immune tolerance.
Abstract: Histone deacetylase inhibitors (HDIs) are a new class of compounds that are being developed for the treatment of malignancies such as cutaneous T-cell lymphoma. HDIs inhibit the removal of acetyl groups from histones. The histone acetylation process is dependent on two enzymes, histone acetyl transferase (HAT) and histone deacetylase (HDAC), and regulates the expression of genes, including those encoding cell survival or apoptosis. In addition to regulating cell growth, HDIs exert anti-inflammatory effects by controlling the production of anti-inflammatory cytokines; modulating the function of cells such as T cells, monocytes-macrophages, chondrocytes, and osteoclasts; and modulating angiogenesis. In several animal models of arthritis, HDIs improve the clinical manifestations and prevent damage to the bone and cartilage. In humans, the only relevant data available so far come from studies of HAT and HDAC expression in the synovial membrane of patients with rheumatoid arthritis. HDIs may hold promise for the treatment of inflammatory joint disease.
Abstract: The human immunodeficiency virus-1 (HIV-1) is a member of the lentivirus genus. The virus does not rely exclusively on the host cell machinery, but also on viral proteins that act as molecular switches during the viral life cycle which play significant functions in viral pathogenesis, notably by modulating cell signaling. The role of HIV-1 proteins (Nef, Tat, Vpr, and gp120) in modulating macrophage signaling has been recently unveiled. Accessory, regulatory, and structural HIV-1 proteins interact with signaling pathways in infected macrophages. In addition, exogenous Nef, Tat, Vpr, and gp120 proteins have been detected in the serum of HIV-1 infected patients. Possibly, these proteins are released by infected/apoptotic cells. Exogenous accessory regulatory HIV-1 proteins are able to enter macrophages and modulate cellular machineries including those that affect viral transcription. Furthermore HIV-1 proteins, e.g., gp120, may exert their effects by interacting with cell surface membrane receptors, especially chemokine co-receptors. By activating the signaling pathways such as NF-kappaB, MAP kinase (MAPK) and JAK/STAT, HIV-1 proteins promote viral replication by stimulating transcription from the long terminal repeat (LTR) in infected macrophages; they are also involved in macrophage-mediated bystander T cell apoptosis. The role of HIV-1 proteins in the modulation of macrophage signaling will be discussed in regard to the formation of viral reservoirs and macrophage-mediated T cell apoptosis during HIV-1 infection.
Abstract: Monocytes/macrophages are key cells in the pathogenesis of human CMV (HCMV) infection, but the in vitro rate of viral production in primary human monocyte-derived macrophages (MDM) is considerably lower than in fibroblasts. Considering that the NF-kappaB signaling pathway is potentially involved in the replication strategy of HCMV through efficient transactivation of the major immediate-early promoter (MIEP), efficient viral replication, and late gene expression, we investigated the composition of the NF-kappaB complex in HCMV-infected MDMs and fibroblasts. Preliminary studies showed that HCMV could grow in primary MDM culture but that the viral titer in culture supernatants was lower than that observed in the supernatants of more permissive MRC5 fibroblasts. EMSA and microwell colorimetric NF-kappaB assay demonstrated that HCMV infection of MDMs increased p52 binding activity without activating the canonical p50/p65 complex. Moreover, Bcl-3 was up-regulated and was demonstrated to associate with p52, indicating p52/Bcl-3 complexes as the major component of the NF-kappaB complex in MDMs. Luciferase assays in promonocytic U937 cells transfected with an MIEP-luciferase reporter construct demonstrated MIEP activation in response to p52 and Bcl-3 overexpression. Chromatin immunoprecipitation assay demonstrated that p52 and Bcl-3 bind the MIEP in acutely HCMV-infected MDMs. In contrast, HCMV infection of MRC5 fibroblasts resulted in activation of p50/p65 heterodimers. Thus, activation of p52/Bcl-3 complexes in MDMs and p50/p65 heterodimers in fibroblasts in response to HCMV infection might explain the low-level growth of the virus in MDMs vs efficient growth in fibroblasts.
Abstract: Recent studies indicate that TNF (tumor necrosis factor) receptor signalling is a key player in HIV infection. HIV proteins have been shown to target TNF receptor signalling, leading both to apoptosis of uninfected bystander T cells and to sustained viral replication in infected T cells and macrophages. This article proposes a model that highlights the role of HIV proteins in the modulation of TNF receptor signalling and could explain both immune suppression and the formation of viral reservoirs during HIV infection.
