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Biomedical subjects

Maria T Rugeles

Publications and source records attributed to Maria T Rugeles.

8 recordsLinked to original sources
PubMed2006

Defective antigen-presenting cell function in human neonates.

Immaturity of the immune system has been suggested as an underlying factor for the high rate of morbidity and mortality from infections in newborns. Functional impairment of neonatal T cells is frequently quoted as the main underlying mechanism for such immaturity. However, recent studies suggest that neonatal antigen-presenting cells (APCs) also exhibit functional alterations, which could lead to secondary defects of adaptive T-cell responses. In this review, we summarize what is known on the functionality of APC at birth and during early childhood. Compared to adults, neonatal APCs display markers of immaturity and produce low levels of cytokines. Multiple factors could be involved in neonatal APC alteration, such as intrinsic immaturity, defective interaction between APCs and T cells and regulatory T-cell-mediated inhibition. Characterization of the relative contribution of each mechanism is clearly needed to better understand the functional capability of the neonatal immune system.

Animals↗
PubMed2006

Ribonucleases in HIV type 1 inhibition: effect of recombinant RNases on infection of primary T cells and immune activation-induced RNase gene and protein expression.

Ribonucleases (RNases) have therapeutic potential against cancer and viral diseases and have been reported to inhibit replication of the human immunodeficiency virus type 1 (HIV-1) in chronically infected cell lines. The ribonuclease eosinophil-derived neurotoxin (EDN) is responsible for the anti-HIV-1 activity of a soluble factor produced in response to human alloantigens (ASF). Four recombinant RNases (EDN; a four amino acid extension of the N-terminus EDN, -4EDN; RNase A; and angiogenin) were tested for inhibition of HIV-1 replication in PHA blasts. All RNases showed anti-HIV-1 activity, irrespective of whether the RNases were added before, during, or 2 h after infection. Polyclonal antibodies against the four RNases blocked the antiviral activity. ASF inhibited HIV-1 replication in vitro if added up to 4 h after infection. We demonstrated that allostimulation induced EDN, RNase A, and angiogenin mRNA expression in peripheral blood mononuclear cells (PBMCs), although only EDN protein was detected. We identified monocytes and dendritic cells, but not macrophages or T cells, as EDN-producing cells. These findings raise the possibilities that multiple naturally occurring RNases may contribute to protection against HIV-1 infection and could be considered for utilization in HIV-1 therapy.

Analysis of Variance↗
PubMed2006

Innate immune defenses in HIV-1 infection: prospects for a novel immune therapy.

HIV-1 infection leads to a severe decrease of CD4(+) T lymphocytes, dysregulation of several leukocyte subpopulations and generalized immune activation, with the subsequent development of opportunistic infections and malignancies. Administration of highly active antiretroviral therapy (HAART) has been successful in reducing HIV-1 plasma viremia; however, the ability of HAART to restore immunocompetence appears incomplete, particularly in patients with chronic and advanced disease. Several components of the innate immune system have direct anti-HIV-1 effects, and studies to analyze the benefits of enhancing the function of the innate response during HIV-1 infection are increasing. Development of any complementary therapeutic approaches to HIV-1 infection, particularly those able to compensate for the limitations of HAART, and enhance the anti-HIV-1 innate immune activity would be of interest. The stimulation of innate immune responses using Toll-like receptor agonists, such as monophosphoryl lipid A and oligodeoxynucleotides with CpG motifs, are currently being investigated and their benefit in HIV-1-infected patients are under evaluation.

Anti-HIV Agents↗
PubMed2005

Requirement of an additional Sam68 domain for inhibition of human immunodeficiency virus type 1 replication by Sam68 dominant negative mutants lacking the nuclear localization signal.

Human immunodeficiency virus type 1 (HIV-1) replication requires active nuclear export of unspliced and incompletely spliced HIV-1 RNA transcripts. This process is evolutionally made possible by expression of HIV-1 Rev, one of the three HIV-1 proteins encoded by completely spliced HIV-1 RNAs. Evidence has accumulated to suggest that Sam68 plays an important role in HIV-1 replication through HIV-1 Rev protein. In the present study, we further examined the structure-function relationship of Sam68 protein in relation to HIV-1 replication. We identified a Sam68 domain located between aa269 and aa321 to be involved in the HIV-inhibitory effects of Sam68 dominant negative mutants lacking the nuclear localization signal (NLS). Deletion of this domain abrogated inhibition of HIV-1 replication by these mutants. HIV-1 Rev protein appeared to mediate the HIV-inhibitory effects of these mutants and by this domain, as assessed by Rev-dependent chloramphenicol acetyltransferase reporter gene assay, in trans rev-defective HIV-1 complementation assay, and RNase protection assay. The HIV-inhibitory mutants containing this domain were further found to have diminished binding affinity to the wild-type Sam68 and to be associated with cytoplasmic retention of exclusively nuclear localized wild type Sam68. Taken together, these results further ascertain the important role of Sam68 in HIV-1 Rev function and viral replication, and suggest that the HIV-inhibitory effects of Sam68 dominant negative mutants directly result from their binding to endogenous Sam68 and their interference with nuclear localization of endogenous Sam68.

Adaptor Proteins, Signal Transducing↗
PubMed2004

HIV-1 interaction with human mannose receptor (hMR) induces production of matrix metalloproteinase 2 (MMP-2) through hMR-mediated intracellular signaling in astrocytes.

Astrocytes are susceptible to HIV-1 infection. We have recently demonstrated that human mannose receptor (hMR) is directly involved in CD4-independent HIV-1 infection of astrocytes. The apparent paradox between the vivid binding affinity of HIV-1 gp120 protein to hMR and the low efficiency of hMR-mediated HIV-1 infection raises the possibility that HIV-1 binding to hMR alone may negatively affect astrocyte function. In this study, we examined the relationship between HIV-1 interaction with hMR and the production of matrix metalloproteinases (MMPs) in astrocytes. We took advantage of an astroglial cell line U87.MR stably expressing hMR as an in vitro astrocyte model system and human primary astrocytes, and demonstrated that HIV-1 binding to astrocytes induced the production of MMP-2. This induction appeared to be most potent with M-tropic HIV-1 viruses. Increased MMP-2 production was not due to hMR-mediated HIV-1 entry and/or HIV-1 viral gene expression, as the transfection of HIV-1 proviral DNA did not result in MMP-2 production, and the infection of AT-2-treated HIV-1 viruses did not inhibit MMP-2 production. Direct involvement of hMR in HIV-induced MMP-2 production was confirmed by the inhibition of the yeast mannan, an hMR ligand antagonist, and an anti-hMR serum. Furthermore, HIV-induced MMP-2 production in astrocytes was shown to involve hMR-mediated intracellular signaling. Taken together, these results suggest that HIV-1 binding to astrocytes in the absence of HIV-1 viral entry is sufficient to alter astrocyte function through hMR-mediated intracellular signaling. In addition, these results provide new evidence to support the notion that hMR is capable of eliciting intracellular signaling upon ligand binding.

Astrocytes↗
PubMed2003

Standardization of bovine macrophage monolayers and isolation and culture of trypanosomes.

We describe a method for culturing over 90% pure bovine macrophages from peripheral blood mononuclear cells separated with Nycoprep. The cells were cultured for 12 days and then stained with esterase and with anti CD14 to test for purity. The method is reproducible and ensures an adequate number of cells for immunological research. Additionally, we report the unexpected finding of Trypanosoma trypomastigotes in our macrophage cultures from bovines belonging to a geographic area from which no bovine trypanosomes had been reported before.

Animals↗
PubMed2003

Ribonuclease is partly responsible for the HIV-1 inhibitory effect activated by HLA alloantigen recognition.

OBJECTIVE: This study was performed to determine whether ribonucleases (RNases) contribute to the soluble HIV-1 inhibitory activity that results from the recognition of HLA alloantigens. DESIGN AND METHODS: Supernatants from mixed lymphocyte reactions of peripheral blood mononuclear cells from healthy HLA-discordant individuals exhibited HIV-1 inhibitory activity (alloantigen-stimulated factors; ASF). These supernatants were tested for their sensitivity to heating (90 degrees C for 3 min), and for the presence of three RNases belonging to the RNase A superfamily: eosinophil-derived neurotoxin (EDN); RNase A; and angiogenin. Polyclonal antibodies specific for these RNases were used for Western blot analysis of the ASF, as well as for blocking the HIV-1 inhibitory activity of ASF. In addition, an RNase inhibitor (RI) was used to determine whether the anti-viral activity of ASF was due to RNase activity. RESULTS: HIV-1 inhibitory activity of ASF was: (i). resistant to heat treatment; (ii). blocked by 58% with an antibody specific for EDN, but not with antibodies against RNase A or angiogenin; and (iii) blocked by 65-100% with an RI. Moreover, Western blot analysis with an anti-EDN antibody detected EDN in the ASF. CONCLUSION: These findings indicate that the majority of the soluble HIV-1 inhibitory activity contained in the supernatants of mixed lymphocyte reactions is due to EDN or a closely related RNase.

Antiviral Agents↗