1,721,233 research outputs found
THE EFFECT OF CYTOKINES AND PHARMACOLOGICAL AGENTS ON CHRONIC HIV-INFECTION
No full textThe ability of the human immunodeficiency virus (HIV) to replicate in CD4+ T lymphocytes and mononuclear phagocytes(MP) is strongly influenced by immunoregulatory cytokines. In the T cell system, interleukin-2 (IL-2) provides a mitogenic signal leading to both cell proliferation and virus replication. Among other HIV-inductive cytokines, only tumor necrosis factor-alpha or -beta (TNF-alpha/-beta) have been shown thus far to trigger virus expression both in T cells and MP. The mechanism of action of TNF involves the activation of the cellular transcription factor NF-kB which binds to specific consensus sequences present in the enhancer region of the HIV proviral LTR. In addition, several other cytokines (including colony stimulating factors, IL-1, IL-3, and IL-6) have demonstrated upregulatory effects on HIV production in MP, whereas nonimmune interferons (INF-alpha/-beta) have been shown to suppress HIV replication in T cells and MP by acting at different phases in the virus life cycle. Finally, cytokines such as TGF-beta, IFN-gamma, and IL-4 have demonstrated either upregulatory or suppressive effects on virus expression depending on the experimental conditions. This scenario indicates that HIV expression is under the control of a complex network of immunoregulatory cytokines, in addition to its own endogenous regulatory proteins, suggesting that new pharmacologic strategies may be aimed at either mimicking or interrupting cytokine-dependent virus expression. In this regard, a number of different physiologic and pharmacologic agents capable of interfering with cytokine-mediated events, including glucocorticoids, anti-oxidants, such as N-Acetyl-L-Cysteine (NAC), and retinoic acid (RA) have already been shown to profoundly affect HIV replication in vitro
IL-10 SYNERGIZES WITH MULTIPLE CYTOKINES IN ENHANCING HIV PRODUCTION IN CELLS OF MONOCYTIC LINEAGE
No full textSeveral cytokines, whose expression is increased in human immunodeficiency virus (HIV)-infected individuals, can enhance virus replication in CD4(+) T lymphocytes and mononuclear phagocytes (MP). We have previously reported that interleukin (IL)-10 inhibited HIV replication in acutely infected monocyte-derived macrophages (MDM) at concentrations that completely blocked the production of endogenous tumor necrosis factor-alpha (TNF-alpha) and IL-6 from infected cells. In the present study, lower concentrations of IL-10, which were unable to completely suppress endogenous cytokines, paradoxically enhanced HIV replication in MDM induced by other cytokines. This synergistic induction of HIV expression by IL-10 in combination with TNF-alpha, IL-6, and other cytokines was also observed in the chronically infected promonocytic cell line, U1. The enhancing effect of IL-10 was correlated with an increase in HIV mRNA accumulation and potentiation of phorbol ester-induced long terminal repeat-driven transcription that was independent of the NF-kappa B and Spl transcription factors. Thus, IL-10 is a cytokine capable of exerting complex regulatory effects on HIV expression in MP as a function of its own concentration and of the presence of other HIV regulatory cytokines
ALPHA-INTERFERON SUPPRESSES VIRION BUT NOT SOLUBLE HUMAN-IMMUNODEFICIENCY-VIRUS ANTIGEN PRODUCTION IN CHRONICALLY INFECTED T-LYMPHOCYTIC CELLS
No full textAlpha interferon (IFN-alpha) is effective in preventing the release of human immunodeficiency virus (HIV) from chronically infected T-lymphocytic (ACH-2) and promonocytic (U1) cell lines stimulated with the phorbol ester phorbol-12-myristate-13 acetate (PMA). In the present study, we observed that together with particle production, shedding of HIV antigen (p24gag) occurs in the T-cell line ACH-2 both constitutively and after stimulation with PMA. IFN-alpha, although effective in suppressing the release of HIV particles, did not inhibit shedding of p24gag into the culture supernatants of either unstimulated or PMA-stimulated cells. These observations may be of relevance in the evaluation of the in vivo efficacy of IFN-alpha-treatment of HIV-infected individuals as determined by levels of p24 antigen in plasma
HIV REPLICATION IN IL-2-STIMULATED PERIPHERAL-BLOOD MONONUCLEAR-CELLS IS DRIVEN IN AN AUTOCRINE PARACRINE MANNER BY ENDOGENOUS CYTOKINES
No full textReplication of HIV is regulated by virus-encoded regulatory proteins, as well as by a variety of cellular factors including cytokines. In the present study, we have investigated the autocrine/paracrine effects of endogenous cytokines on HIV replication in primary PBMCs of healthy HIV seronegative individuals. Addition of rIL-2 to cultures between 0 and 72 h after isolation of PBMCs allowed the replication of primary HIV isolates and laboratory-adapted HIV strains to levels comparable with or greater than those obtained in parallel cultures of autologous PHA-blasts. In this regard, both major cellular targets of HIV infection, CD4(+) T lymphocytes and mononuclear phagocytes, were maintained for several weeks in IL-2-stimulated PBMC cultures and virion production was observed in both cell lineages. The kinetics of secretion of several cytokines (such as TNF-alpha, IL-1 beta, IL-6, and IFN-gamma), as well as expression of cellular activation markers, paralleled HIV replication in IL-2-stimulated PBMCs. Endogenous pro-inflammatory cytokines and IFN-gamma played a major role in the regulation of HIV replication in IL-2-stimulated PBMCs, as determined by the ability of several anti-cytokine Abs or antagonists to suppress HIV production; this was not the case in parallel cultures of autologous PHA-blasts. Thus, IL-2-stimulated PBMCs may represent a more physiologic in vitro system than PHA-blasts for the study of HIV infection and replication, and should prove useful in investigating the role of cytokines and other host factors in the regulation of HIV production
Activated B lymphocytes from human immunodeficiency virus-infected individuals induce virus expression in infected T cells and a promonocytic cell line, U1.
No full textFreshly isolated B lymphocytes from patients infected with human immunodeficiency virus (HIV), in contrast to B cells from normal controls, were shown to induce viral expression in two cell lines: ACH-2, a T cell line, and U1, a promonocytic cell line, which are chronically infected with HIV, as well as in autologous T cells. In 10 out of 10 HIV-infected individuals with hypergammaglobulinemia, spontaneous HIV-inductive capacity was found with highly purified peripheral blood B cells, whereas peripheral blood or tonsillar B cells from six healthy, HIV-negative donors did not induce HIV expression unless the cells were stimulated in vitro. The induction of HIV expression was observed in direct coculture experiments of B lymphocytes and HIV-infected cells, and could also be mediated by supernatants from cultures of B cells. Significantly higher amounts of interleukin 6 (IL-6) and tumor necrosis factor alpha-(TNF-alpha) were detected in the B cell culture supernatants from HIV-infected patients with hypergammaglobulinemia (IL-6: xbar = 536 pg/ml; TNF-alpha: xbar - 493 pg/ml), as compared with normal uninfected controls (IL-6: xbar = 18 pg/ml; TNF-alpha: xbar = 23 pg/ml). Antibodies against these cytokines abolished the HIV-inductive capacity of B cells. We conclude that in vivo activated B cells in HIV-infected individuals can upregulate the expression of virus in infected cells by secreting cytokines such as TNF-alpha and IL-6, and, therefore, may play a role in the progression of HIV infection
Selection of HIV-specific immunogenic epitopes by screening random peptide libraries with HIV-1-positive sera
No full textEfforts to develop a protective HIV-1 vaccine have been hindered by difficulties in identifying epitopes capable of inducing broad neutralizing Ab responses. In fact, the high mutation rate occurring in HIV-1 envelope proteins and the complex structure of gp120 as an oligomer associated with gp41 result in a high degree of antigenic polymorphism. To overcome these obstacles, we screened random peptide libraries using sera from HIV-infected subjects to identify antigenic and immunogenic mimics of HIV-1 epitopes. After extensive counterscreening with HIV-negative sera, we isolated peptides specifically recognized by Abs from HIV-1-infected individuals. These peptides behaved as antigenic mimics of linear or conformational HIV-1 epitopes generated in vivo in infected subjects. Consistent with these findings, sera of simian HIV-infected monkeys also recognized the HIV-specific epitopes. The selected peptides were immunogenic in mice, where they elicited HIV-specific Abs that effectively neutralized HIV-1 isolates. These results demonstrate that pools of HIV-1 mimotopes can be selected from combinatorial peptide libraries by taking advantage of the HIV-specific Ab repertoire induced by the natural infection
4F2 monoclonal antibody recognizes a surface antigen on spread human fibroblasts of embryonic but not of adult origin.
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