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

This chapter has summarized studies showing that cells of the immune system and glial cells of the CNS use many of the same cytokines as communication signals. Activated astrocytes and microglia are the principal sources of these cytokines in the CNS, although oligodendrocytes are capable of expressing IL-1 and TGF-beta. There is a complex circuitry of interactions mediated by cytokines, especially in the event of blood-brain barrier damage and lymphoid/mononuclear cell infiltration into the CNS. Infiltrating activated macrophages produce cytokines such as IL-1, TNF-alpha, and IL-6, which would trigger glial cells to produce their own cytokines. The activation of astrocytes and microglia to secrete proinflammatory cytokines such as IL-1, TNF-alpha, IL-6, and GM-CsF may contribute to the propagation of intracerebral immune and inflammatory responses initiated by immune cells, as well as enhancement of HIV-1 expression in the CNS. The cytokine cascades ongoing in the CNS could ultimately be suppressed due to the presence of immunosuppressive cytokines such as TGF-beta. Whether immune and inflammatory responses within the CNS are propagated or suppressed depends on a number of parameters, including (a) the activational status of these cells, (b) cytokine receptor levels on glial and immune cells, (c) the presence of cytokines with both immune-enhancing and immune-suppressing effects (IFN-gamma, IL-1, TNF-alpha, IL-6, TGF-beta, CsFs), (d) the concentration and location of these cytokines in the CNS, and (e) the temporal sequence in which a particular cell is exposed to numerous cytokines (see Fig. 1). The ultimate outcome of immunologic and inflammatory events in the CNS, as well as HIV expression, will be determined, in part, by an interplay of the above parameters.
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PMID:Cytokine circuits in brain. Implications for AIDS dementia complex. 811 22

In addition to CD4, the primary receptor to which the human immunodeficiency virus type 1 (HIV-1) binds, mononuclear phagocytes (monocytes) express three classes of Fc receptors for immunoglobulin G (Fc gamma R). We have previously shown that infection of monocytes by HIV-1 is inhibited when bispecific antibodies (BsAbs) are used to target the virus to either the type I, type II, or type III Fc gamma R on these cells. Infection of monocytes was not inhibited when HIV-1 was targeted to either human leukocyte antigen class I or CD33. We have extended these studies to examine the ability of BsAbs plus polymorphonuclear leukocytes (neutrophils, PMNs) and monocytes to reduce infectivity of HIV-1 to cells from the human T cell lymphoma line, H9. The production of HIV-1 following interaction of virus with BsAb and phagocytes was determined in an indicator cell assay by mixing BsAb, HIV-1, and phagocytes with uninfected H9 cells. Productive infection of H9 cells was quantitated on subsequent days by measuring p24 gag antigen levels in supernatants by enzyme-linked immunosorbent assay. Our findings show that the addition of interferon-gamma-activated PMNs or monocytes to cultures of HIV-1 plus H9 cells in the absence of BsAb results in a marked reduction in p24 levels equivalent to 85 to 90% of control levels. With the combination of BsAb (anti-Fc gamma RI x anti-gp120) plus IFN-gamma-activated phagocytes, levels of p24 in H9 cultures were below those at culture initiation. These findings demonstrate that IFN-gamma-activated phagocytes can affect the natural course of HIV-1 infection of T cells, a finding of potential clinical importance.
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PMID:Targeting HIV-1 to Fc gamma R on human phagocytes via bispecific antibodies reduces infectivity of HIV-1 to T cells. 812 Apr 55

Evidence has been presented for the involvement of IFN-gamma, IL-4 and TGF-beta in AIDS. Measured plasma levels may, however, poorly reflect in vivo production, since cytokines act auto- and paracrinally and have very short half life in plasma. In situ hybridization with complementary DNA oligonucleotide probes was used to enumerate blood mononuclear cells expressing cytokine messenger RNA (mRNA). HIV-infected patients had elevated blood levels of cells expressing each of the cytokines, with predominance for cells expressing TGF-beta mRNA. All AIDS patients included had elevated numbers of IL-4 mRNA-expressing cells, and levels of cells expressing this cytokine correlated inversely with counts of CD4+ cells in blood, reflecting the involvement of Th2-like cells in later stages of HIV infection. The described approach should be useful in further studies of cytokines in HIV infection and other diseases.
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PMID:Increased levels of interferon-gamma (IFN-gamma), IL-4 and transforming growth factor-beta (TGF-beta) mRNA expressing blood mononuclear cells in human HIV infection. 814 67

SIVsmmPBJ 1.9 is an extremely virulent clone of the simian immunodeficiency virus SIVsmmPBj 14 that causes an acute lethal disease in pigtail macaques, with death occurring 6 to 8 days after infection. The disease is characterized by bloody mucoid diarrhea, lymphoid hyperplasia, and giant cell pneumonia. We have developed an in vitro model for the production of multinucleated giant cells (MGCs) in which peripheral blood monocytes rapidly fuse to form MGCs when cultured in lymphocyte-conditioned medium and antibody against class II MHC. We have tested the effect of SIVsmmPBj on monocytes in our MGC model system. Peripheral blood mononuclear cells (PBMCs) from normal healthy human subjects, when cultured in the presence of anti-class II MHC monoclonal antibody and SIVsmmPBj 1.9, but not either alone, resulted in the formation of MGCs within 4 days. Experiments using Transwell chambers indicated that such MGCs are formed by fusion of monocytes, not by virus-induced fusion of lymphocytes. SIVsmmPBj 1.9 is unique in inducing MGC formation in that other SIV and HIV isolates do not induce MGCs. Whereas SIVsmmPBj 1.9 grown in PBMCs was a potent inducer of MGCs in the presence of anti-class II MHC antibody, SIVsmmPBj 1.9 grown in CEMx174 failed to do so. Antibodies against IFN-gamma and TNF-alpha significantly inhibited SIVsmmPBj/anti-class II-induced formation of MGCs. These results indicate that cytokines released in response to SIVsmmPBj 1.9, in conjunction with antibodies to class II MHC, caused fusion of monocytes.
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PMID:Simian immunodeficiency virus SIVsmmPBj 1.9 induces multinucleated giant cell formation in human peripheral blood monocytes. 817 65

To analyze the molecular interactions involved in CD8+ cytotoxic T lymphocyte (CTL) recognition quantitatively, we developed a cell-free antigen presenting system. Genetically engineered soluble H-2Dd molecules coated on plastic microtiter plates could present HIV envelope peptide to an antigen-specific CTL clone, inducing it to produce IFN-gamma in the absence of accessory cells and their accessory or co-stimulatory molecules. The peptide-MHC complexes were functionally stable for over 24 h. The magnitude of T cell activation was dependent on the concentrations of both class I MHC molecule and the peptide, but was more sensitive to the concentration of the MHC molecule than to that of peptide. This result suggests that one MHC molecule can play more than one role in activating the CTL. One such role is the interaction between CD8 and a conserved region of class I MHC, as suggested by the finding that holding the total MHC concentration constant with an irrelevant class I MHC molecule (H-2Kb engineered to have the same alpha 3 domain as H-2Dd) made the T cell response less sensitive to the change in concentration of the relevant MHC molecule (H-2Dd). The irrelevant class I MHC molecule (H-2Kb), unable to present this peptide by itself, augmented the T cell response at lower concentrations of peptide. These results suggest that the conserved alpha 3 domain of the class I MHC heavy chain as well as polymorphic regions play an important role in T cell activation and that T cell interaction with MHC molecules not presenting peptide can still augment the response.
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PMID:Role of conserved regions of class I MHC molecules in the activation of CD8+ cytotoxic T lymphocytes by peptide and purified cell-free class I molecules. 824 Oct 55

Based on our finding that HIV-1 gp41 independently of CD4 can bind to several proteins (gp41 binding protein: GBP) on the human T-cell line H9, B-cell line Raji and monocyte-cell line U937, we examined the effect of mitogens and cytokines on binding of gp41 to H9, Raji and U937 cells. Flow cytometry (FACS) analysis demonstrated that PWM and LPS, IFN-gamma and IL-6, but not Con A, IFN-alpha, -beta, -omega and IL-2, could increase gp41 binding to Raji cells. In controls, none of the regulators (IFN-alpha, -beta, -gamma, -omega, IL-2, IL-6, Con A, PWM, LPS) could modify the binding potential of H9 and U937 cells. Our data suggest that the expression of HIV-1 binding proteins is subject to regulation by PWM, LPS, IFN-gamma and IL-6 in the case of B-cells, while on T-cells and macrophages, the binding proteins may be constitutively expressed.
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PMID:Enhancement of HIV-1 gp41 binding to Raji cells by PWM, LPS, interferon-gamma and interleukin-6. 824 28

A mannoprotein fraction (MP-F2: mannan, > 90%; protein, 4.5%) from the human commensal microorganism Candida albicans was as efficient as interleukin-2 (IL-2) in generating cytotoxicity against the uninfected or human immunodeficiency virus type-1 (HIV-1) persistently infected monocytoid U937 cell line in cultured peripheral blood mononuclear cells (PBMC) from healthy human subjects. MP-F2-activated killing of U937 cells (U937-MAK) decreased progressively with advancing stages of HIV-1 infection to virtually no killing effect in PBMC from advanced AIDS subjects (AIDS PBMC). This decrease paralleled a lowered susceptibility of U937 cells to natural killer cell activity. In contrast, IL-2-activated killing of U937 cells (U937-LAK) was not affected by the progression of HIV infection and persisted at high levels in AIDS PBMC. To shed light on the mechanisms of U937-MAK and its decrease during HIV infection, IL-1 beta, IL-6, TNF-alpha, GM-CSF, and IFN-gamma production was analyzed. Decreases in TNF-alpha, GM-CSF, and IFN-gamma, but not IL-1 beta or IL-6, levels were observed in MP-F2-stimulated PBMC from HIV-infected subjects, compared to healthy controls. Interestingly, these cytokine levels fell before the onset of AIDS. The greatest relative drop was that of IFN-gamma, from 4600 (+/- 600) to 290 (+/- 160) and 217 (+/- 110) mean pg/ml (+/- SE) in PBMC from healthy donors (11 subjects), CDC stages II + III (14 subjects), and CDC stage IV (10 subjects), respectively. The following observations suggest that decreased IFN-gamma production plays a role in the abrogation of U937-MAK activity: (i) addition of neutralizing anti-IFN-gamma antibodies abolished both IFN-gamma and U937-MAK activity in PBMC from healthy subjects; (ii) substantial levels of IFN-gamma were detected in supernatants of PBMC cultures stimulated by IL-2, in line with preserved U937-LAK activity. Interestingly, anti-IFN-gamma antibodies also abolished TNF-alpha production, and the anti-TNF-alpha antiserum effect was comparable to that of anti-IFN-gamma in U937-MAK inhibition. In contrast, anti-TNF-alpha antibodies abrogated TNF-alpha activity, but only partially reduced IFN-gamma production. Thus, in human PBMC, U937-MAK activity progressively decreases with advancing stages of HIV infection, whereas U937-LAK activity is sustained. Furthermore, the present results indicate a pivotal role for IFN-gamma in U937 MAK activity, possibly through activation of TNF-alpha production.
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PMID:Mannoprotein-induced anti-U937 cell cytotoxicity in peripheral blood mononuclear cells from uninfected or HIV-infected subjects: role of interferon-gamma and tumor necrosis factor-alpha. 825 54

The T2 mutant cell line is unable to load peptides into the MHC class I Ags inside the cells. These "empty" MHC class I Ags are not expressed on the cell surface unless the cells are cultured at low temperatures. Expression will occur at 37 degrees C only in the presence of peptides that bind to and stabilize the class I Ags. T2 cells transfected with the B*2705 gene were tested with a panel of anti-HLA-B27 mAb. Two of the antibodies, ME1 and KS3, reacted with the "empty" HLA-B27 expressed at low culture temperatures. Three antibodies, B27.M1, B27.M2, and Ye-2, were unreactive with these "empty" HLA-B27. The cells were then incubated with a panel of HLA-B27-binding peptides. One of the antibodies, Ye-2, became reactive when the cells were incubated with a peptide derived from HIV gp120 and to a less degree with a peptide derived from histone H3.3. Mouse L cells transfected with the B*2705 and the human beta 2m genes also reacted very poorly with B27.M1, B27.M2, and Ye-2. Those two peptides were also able to induce high increase in Ye-2 reactivity. Alternately, increase in Ye-2 reactivity was also observed when the L cells were incubated with IFN-gamma or TNF-alpha. These experiments indicate that the Ye-2 anti-HLA-B27 mAb recognizes HLA-B27 in the context of certain residing peptides either added exogenously or expressed endogenously. The B27.M1 and B27.M2 antibodies might share similar characteristics.
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PMID:A monoclonal antibody that recognizes HLA-B27 in the context of peptides. 830 Nov 24

CD8-positive cytotoxic T cells (CTLs) are activated by recognition of peptide bound to MHC class I molecules on target cells. This human leukocyte antigen-restricted process induces not only lysis of target cells but also secretion of lymphokines by the CTLs, including TNF-alpha, TNF-beta, and IFN-gamma. In this study we show that activation of HIV-1-specific CTL clones by their cognate peptide epitopes induces HIV-1 replication in the chronically HIV-1-infected T-cell line ACH-2. The HIV-1-inducing activity correlates with increased levels of TNF-alpha produced by these CTLs, and can be inhibited by anti-TNF-alpha antibodies, indicating that the effect is mediated by this cytokine. These studies suggest that activation of CTL in vivo could lead to enhanced viral replication. Although HIV-1-specific CTLs may serve as a host defense to inhibit virus replication, the induction of TNF-alpha production by these cells may facilitate viral replication in infected bystander cells, contributing to viral persistence and disease pathogenesis.
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PMID:Induction of HIV-1 replication in a chronically infected T-cell line by cytotoxic T lymphocytes. 831 73

IFN-alpha is in plasma of HIV-1 infected patients during early and late-stage disease and may play a role in control of virus replication. The stimulus for IFN-alpha production, the cells that produce this cytokine, and the effectiveness of this IFN-alpha response for control of virus infection are not yet defined. Culture fluids from freshly isolated PBMC of HIV-1 seronegative donors contained high levels of IFN-alpha after exposure to 100 to 1000 infectious HIV-1 particles per culture. Levels of IFN-alpha induced by HIV-1 were directly dependent on the number of monocytes in cell preparations: No IFN-alpha was detected from T cell-enriched PBMC. In monocyte cultures, induction of IFN-alpha by HIV-1 was relatively specific: Levels of IL-1 beta, IL-6, IFN-gamma, and TNF-alpha remained at baseline. Capacity of HIV-1 virions to induce IFN-alpha was not dependent on virus replication. IFN-alpha was induced by (a) heat-inactivated HIV-1, (b) virions from 8E5 cells, a cell line that releases noninfectious HIV-1, (c) HIV-1-infected cells fixed in paraformaldehyde, and (d) T cell-tropic HIV-1 that binds to but does not infect monocytes. Capacity of HIV-1 virions and HIV-1 infected cells to induce IFN-alpha was completely inhibited by soluble rCD4 or mAb against CD4 or gp120. Antibodies against CD4, however, did not induce monocytes to produce IFN-alpha. HIV-1-induced IFN-alpha production was inhibited by antibodies against both V3 loop determinants and the CD4 binding site of gp120. Further, sera and purified immunoglobulin from HIV-1 infected patients also inhibited HIV-1-induced IFN-alpha production. These observations suggest that potentially protective antiviral responses associated with IFN-alpha production in HIV-1 infected patients are inhibited by the development of antibodies against gp120.
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PMID:Induction of IFN-alpha by HIV-1 in monocyte-enriched PBMC requires gp120-CD4 interaction but not virus replication. 834 4


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