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Query: UMLS:C0019693 (HIV)
170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There still remains several unanswered questions concerning the pathogenesis of human immunodeficiency virus (HIV) infection. Interferons (IFNs), as well as other cytokines, are both dysregulated in HIV infection and serve as effector molecules that modulate the replicative capacity of HIV. Acid-labile IFN-alpha, an aberrant form of interferon earlier described in certain autoimmune diseases, has been detected in HIV-infected individuals. Conversely, a deficient expression of IFN-alpha may occur usually associated with HIV disease. Although conflicting findings have been reported on whether IFN-gamma, a product of activated T and natural killer (NK) cells, is elevated in the peripheral blood (PB) compartment, high levels of its expression have been observed in the germinal centers of the lymph nodes during HIV disease. IFN-alpha and IFN-beta have shown potent anti-retroviral effects in several in vitro systems of both acute and chronic HIV infection. These findings have served as the basis of the rationale for their therapeutic application, resulting in some positive effects at least in those patients with relatively high CD4+ T cell counts and healthy immune functions. Furthermore, IFN-alpha has shown important therapeutic effects on HIV-associated Kaposi's sarcoma (KS). Both suppressive and inductive effects on HIV replication in vitro have been described for IFN-gamma, whereas no clear clinical benefits have been reported following its administration to HIV-infected individuals. In conclusion, IFNs are involved in several pathogenic aspects of HIV infection and AIDS, and certain IFNs may serve as important tools to limit the spread of the virus and the progression of disease.
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PMID:Interferons in the pathogenesis and treatment of human immunodeficiency virus infection. 752 93

Infection with human immunodeficiency virus type 1 (HIV-1) induces vigorous and persistent cytotoxic CD8+ T cell responses. CTL clones were derived from peripheral blood or cerebrospinal fluid of three HIV-1 patients, with depressed CD4+ T cell counts. When stimulated with HLA-compatible target cells (B-LCL) presensitized with cognate HIV-1 peptides, all clones produced GM-CSF, TNF-alpha, and IFN-gamma and most produced low amounts of IL2, IL3, and IL4. After nonspecific stimulation with a phorbol ester and calcium ionophore, the clones secreted cytokines at levels similar to those from CD4+ lines from an HIV-1 infected donor. The ability of supernatants from the stimulated CTL clones to support the formation of granulocyte-macrophage colonies in normal bone marrow suggests that the GM-CSF was biologically active. Release of cytokines by activated CTL may influence the immunopathogenesis of HIV disease.
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PMID:Cytotoxic CD8+ T lymphocytes reactive with human immunodeficiency virus-1 produce granulocyte/macrophage colony-stimulating factor and variable amounts of interleukins 2, 3, and 4 following stimulation with the cognate epitope. 752 47

We previously reported the expansion during HIV infection of a subset of CD4+ T cells characterized by a lack of CD7 cell surface expression. This CD4+CD7- subset showed in normal donors a lower cell proliferation than CD4+CD7+ autologous cells after CD3 triggering or CD28 costimulation. Our aim was to further characterize the Th function of this CD4+CD7- T cell subset, both in normal donors and in HIV-infected patients. Their CD4+CD7- cell proliferation and cytokine secretion were analyzed after cell-sorting and co-stimulation of the CD3 and CD28 pathways. In normal donors, the IL-2 produced by CD4+CD7- cells in response to a CD3 plus CD28 costimulus represented 50 +/- 28% of the autologous CD4+CD7+ cell IL-2 secretion. In addition, the CD4+CD7+ T cells produced higher amounts of IL-4 and IL-10 than the CD4+CD7+ cells with mean CD4+CD7-: CD4+CD7+ ratios of 5.4 +/- 4.5 and 26 +/- 25, for IL-4 and IL-10, respectively, whereas the IFN-gamma production was similar in both subsets. After a triggering of the CD3 complex alone, significant amounts of IL-2 were detectable in CD4+CD7+ cell supernatants only; conversely, IL-4 and IL-10 could be detected only in the culture medium from CD4+CD7- T cells. This profile of cytokine production was maintained both over time and at the clonal cell level in the CD4+CD7- T cell subset. In HIV-infected patients, the CD4+CD7- T cell expansion observed in relationship with disease progression was associated to an in vivo activation of the CD4+CD7- cells, as assessed by cell surface expression of the HLA-DR, CD25, CD71, and CD57 markers. The CD4+CD7- T cells from HIV-seropositive patients showed the same imbalance of cell proliferation and IL-2, IL-4, and IL-10 production as observed in normal donors despite low levels of proliferation and cytokine production. Together, our data indicate that the lack of CD7 expression defines a CD4+ Th cell subset with a Th0/Th2-like profile of cytokine secretion in normal individuals. The CD4+CD7- subset is expanded during HIV infection and characterized by the same although impaired profile of cytokine production. These CD4+CD7- T cells might play a role in the Th cell dysfunctions observed in HIV infection.
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PMID:A Th0/Th2-like function of CD4+CD7- T helper cells from normal donors and HIV-infected patients. 752 3

Interleukin (IL)-12 was originally identified as a factor produced by human Epstein-Barr virus-transformed B cell lines. It was detected by one group as cytotoxic lymphocyte maturation factor, a cytokine that synergized with IL-2 in the induction of lymphokine-activated killer cells and cytotoxic T lymphocytes. A second group characterized it as a natural killer (NK) cell stimulatory factor, due to the enhancement of cytotoxicity and IFN-gamma synthesis by NK cells. Human IL-12 was purified to homogeneity and cloned by both groups. We had identified a murine factor, provisionally termed T cell-stimulating factor (TSF), which was involved in the proliferation, synthesis of IFN-gamma and cell adhesion of CD4+ Th1 cells. TSF was produced in the antigen-specific interaction between Th1 cells and macrophages as antigen-presenting cells, partially purified from supernatants of such cultures, and shown to be identical to IL-12. Monocytes/macrophages appear to be the major source of IL-12. It is rapidly produced by phagocytic cells after stimulation with several bacteria/bacterial products and other microorganisms. In the light of its effects on NK cells as well as CD4+ and CD8+ T cells, IL-12 can be regarded as a cytokine that connects the innate immune system with the acquired immunity. IL-12 has a broad range of activities already reviewed in three papers. These include the regulation of cytokine synthesis and proliferation of T and NK cells, the promotion of Th1 cell development, the differentiation of CD8+ T cells and effects on hematopoiesis. When applied in vivo, IL-12 was shown to enhance the resistance to bacterial and parasitic infections, to promote antitumor immunity, and to influence antiviral responses including HIV in vivo or in vitro. This review will briefly summarize these effects, but mainly focus on recent results concerning the regulation of the production and the activity of IL-12, its role in the differentiation of Th cells and the implications for delayed- and immediate-type hypersensitivity reactions, its importance for organ-specific autoimmune diseases, and the possible role of the IL-12p40 homodimer as a specific inhibitor of the IL-12 heterodimer.
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PMID:Interleukin-12. 754 96

Patterns of cytokine expression were analyzed in polyclonal and antigenic responses in children with perinatal HIV infection. Responses of PBL to PMA and A23187 calcium ionophore studied in patients in different stages of HIV infection revealed reduced levels of IL-2 in HIV-infected children beginning before 6 mo of age, and age-dependent increases in expression of IL-4, IL-10, and IFN-gamma. The levels of IL-4, IL-10, and IFN-gamma expression did not differ significantly between HIV-infected and age-matched uninfected children of HIV-seropositive mothers, except for a small reduction in HIV-infected children in late stages of infection. Responses to PHA, HLA alloantigens, HIV envelope peptides T1 and P18, and tetanus toxoid were studied in PBMC derived from asymptomatic and mildly symptomatic HIV-infected children. IL-2, IFN-gamma, IL-4, and IL-5 expression was detected in PHA-stimulated PBMC from all analyzed patients. HIV-infected children who failed to respond to HLA alloantigens, tetanus toxoid, or the envelope peptides had lower numbers of CD4+ cells and expressed, on PHA stimulation, higher levels of IL-4 and IL-5 and lower levels of IL-2 and IFN-gamma than patients who responded to the antigenic stimulation. Results of these analyses suggest that cytokine expression in HIV-infected children depends on the character of the stimuli as well as the phenotype of PBMC, and indicate possible prevalence of Th2 Ag-specific responses during the progression of HIV-induced immunodeficiency.
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PMID:Cytokine patterns during progression to AIDS in children with perinatal HIV infection. 756 Nov 17

Cellular adhesion molecules, such as ICAM-1, -2, and -3; LFA-1; and HLA class I and II are incorporated into HIV-1 virions during budding from infected cells. These virion-associated molecules can be involved in the adsorption to susceptible cells displaying the corresponding counterligands. A number of cytokines have been shown to upregulate the cellular expression of adhesion molecules, such as ICAM-1 and HLA-DR. In this study we investigated the effects of IFN-gamma on the incorporation of ICAM-1, LFA-1, and HLA-DR into mature HIV-1 progeny from chronically infected cells. The ability of such virus progeny to infect either CD4-positive or -negative cells was also investigated. The results indicate that IFN-gamma stimulates the expression of ICAM-1 and of HLA-DR on HIV-1-infected cells, whereas LFA-1 expression is unaffected. The same modifications were also observed on virus progeny, because specific MAbs to ICAM-1 and HLA-DR captured infectious HIV-1 from IFN-treated cells with higher efficiency as compared to virus from control cells, whereas virus binding to anti LFA-1 MAb was unchanged. Moreover, the HIV-1 progeny released from IFN-treated cells showed an increased ability to bind to and to infect CD4-negative cells, whereas the infectivity was basically unchanged for CD4-positive cells. Our results suggest that cytokines, as well as other soluble factors, may expand the host cell range of HIV-1, possibly through modifications of the cell-derived surface molecules on the virions.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:HIV type 1 grown on interferon gamma-treated U937 cells shows selective increase in virion-associated intercellular adhesion molecule 1 and HLA-DR and enhanced infectivity for CD4-negative cells. 757 10

While considerable progress in examining the course of human immunodeficiency virus (HIV) infection in adults has been made, a better understanding of the natural history of perinatal HIV infection remains to be obtained. Dysregulation of the production and functions of various cytokines, especially the interferons (IFNs), during HIV infections has been reported. Using an in vitro model system, we examined the effects of the HIV type 1 envelope protein, gp120 (10, 50, and 100 ng/ml), on gamma IFN (IFN-gamma) and IFN-alpha production by lymphocytes from neonates and adults and also examined the potential regulatory effects of gp120 on phorbol 12-myristate acetate (PMA)- and Sendai virus-induced IFN-gamma and IFN-alpha production by lymphocytes. PMA at a concentration of 50 ng/ml plus 50 ng of calcium ionophore A23187 per ml was used to induce IFN-gamma, while 150 hemagglutinating units of Sendai virus was used to induce IFN-alpha production. The antiviral activity of both IFN-alpha and IFN-gamma in leukocyte culture supernatants was assayed on BG-9 cells by a dye uptake technique using vesicular stomatitis virus as a challenge virus. Placental cord blood leukocyte (CBL) samples from healthy, term infants and adult peripheral blood leukocytes (APBL) produced no IFN in response to gp120. However, CBL produced significantly decreased levels of IFN-gamma compared with APBL in response to PMA plus ionophore. gp120 significantly suppressed both Sendai virus-induced IFN-alpha and PMA-induced IFN-gamma production by both CBL and APBL in a dose-dependent manner. However, gp120-induced suppression of IFN-alpha and IFN-gamma was significantly greater with CBL than with APBL. Treatment of CBL and APBL with gp120 did not induce any phenotypic alteration of the CD45 RO+ subset. Increased suppression of IFN-alpha and IFN-gamma production by gp120 in neonates may partially explain their apparent increased susceptibility to the clinical progression of HIV infections compared with that of adults.
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PMID:Differential effects of human immunodeficiency virus type 1 envelope protein gp120 on interferon production by mononuclear cells from adults and neonates. 758 19

Infection with human immunodeficiency virus type 1 (HIV-1) results in dysregulation of normal T cell function. To study the effects of HIV-1 at the cellular level, primary T cell lines were generated by alloantigen stimulation of CD4+ T cells collected from peripheral blood of HIV-1-infected donors. Using Epstein-Barr virus-infected B lymphocytes (EBV-LCL) as a source of alloantigen, the T cell lines were expanded in vitro for 7 weeks. Uninfected T cell lines were cultured in parallel. Virus was inducible from the infected lines with stimulation, and complete infection was achieved after 4-7 weeks depending on the line. The down-modulation of CD28 expression correlated with virus replication and spread. Furthermore, CD28 mRNA was not inducible in the infected lines after stimulation with alloantigen. Loss of CD28 correlated with reduced responsiveness to costimulation with a monoclonal antibody to CD28 following similar engagement of the CD3 protein. In contrast, activation with alloantigen was not affected. HIV-1 infection and down-modulation of CD28 did not alter the relative levels of IL-2, IFN-gamma, and IL-4 mRNA. Production of the various cytokine mRNAs following alloantigen stimulation was inhibited by CTLA4Ig and thus remained under the regulation of CD80 and CD86 expressed on the EBV-LCL. Taken together, our data suggest that dysregulation of normal T cell function associated with HIV-1 infection may result in part form the loss of CD28 expression.
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PMID:Human immunodeficiency virus type 1 infection of CD4+ T cells down-regulates the expression of CD28: effect on T cell activation and cytokine production. 758 36

Individuals infected with Toxoplasma gondii normally develop resistance to the parasite, resulting in an asymptomatic chronic infection. In AIDS patients, this resistance is lost leading to reactivation of infection and development of encephalitis. To characterize the cytokine response of T. gondii-infected individuals, PBMC were cultured in vitro in the presence or absence of crude tachyzoite Ags (STAg). When stimulated with STAg, PBMC from T. gondii-infected donors, but not controls, produced high levels of Type 1 lymphokines (IL-2 and IFN-gamma) as well as the monokine IL-12, in the absence of detectable Type 2 lymphokines (IL-4 and IL-5). In contrast, cells of individuals from both groups produced high levels of IL-1, IL-6, and TNF-alpha when exposed to the same Ag preparation. By using highly purified elutriated cells, we demonstrated that monocytes are a major source of these monokines. The above findings were further expanded by analyzing the cytokine responses induced by STAg in PBMC from patients co-infected with T. gondii and HIV. Our results demonstrate that parasite-specific IL-2 and IFN-gamma responses are greatly impaired even before AIDS development, as is IL-12 synthesis by PBMC from HIV-infected individuals stimulated with STAg. In contrast, the release of IL-6 and TNF-alpha triggered by STAg is either not affected or augmented during HIV infection.
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PMID:HIV infection suppresses type 1 lymphokine and IL-12 responses to Toxoplasma gondii but fails to inhibit the synthesis of other parasite-induced monokines. 763 18

Human immunodeficiency virus type 1 (HIV-1) infection is associated with elevated levels of inflammatory cytokines in the serum and cerebrospinal fluid of infected persons, but the sources of these proteins as well as the specific stimuli which trigger their production and release have not been fully defined. In this study, we evaluated the ability of HIV-1-specific cytotoxic T-lymphocyte (CTL) clones derived from seropositive persons to release gamma interferon (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), and TNF-beta upon contact with target cells presenting viral antigen. Peripheral blood- and cerebrospinal fluid-derived HIV-1-specific CD3+ CD4- CD8+ CTL clones as well as freshly isolated peripheral blood mononuclear cells from infected persons were tested in parallel for HIV-1-specific cytotoxicity and cytokine release. Target cells consisted of autologous and allogeneic B-lymphoblastoid cell lines sensitized with synthetic HIV-1 peptides containing the epitopes recognized by these CTL. Cytokine production was measured by specific enzyme-linked immunosorbent assay of culture supernatant fluid. HIV-1-specific CTL clones directed at envelope, Gag, reverse transcriptase, and Nef epitopes specifically released IFN-gamma, TNF-alpha, and TNF-beta upon contact with their relevant target epitopes but not following contact with irrelevant epitopes. These cytokines were released in an HLA class I-restricted fashion, and release was detectable as early as 4 to 6 h of incubation and remained elevated at 48 h. Fresh peripheral blood mononuclear cells from a seropositive person likewise released IFN-gamma in an antigen-specific and HLA class I-restricted manner when incubated with target cells presenting a peptide containing a CTL epitope, paralleling the HIV-specific cytolytic activity of these cells. These studies indicate that in addition to mediating direct cytotoxicity, HIV-1-specific CTL may affect other immune responses by releasing IFN-gamma, TNF-alpha, and TNF-beta. Elevated levels of these cytokines which have been detected in serum and cerebrospinal fluid of infected persons may be due at least in part to the persistent HIV-1-specific CTL response.
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PMID:Human immunodeficiency virus type 1-specific cytotoxic T lymphocytes release gamma interferon, tumor necrosis factor alpha (TNF-alpha), and TNF-beta when they encounter their target antigens. 768 29

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