Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CD8+ T-cell clones were generated from peripheral blood mononuclear cells (PBMC) of three human immunodeficiency virus (HIV)-seronegative individuals and six HIV-seropositive individuals and assessed for their cytokine secretion profile, cytolytic potential, and chemokine production. While the great majority of CD8+ T-cell clones generated from HIV-seronegative individuals produced interferon (IFN)-gamma, but not interleukin-4 (IL-4), that is a type 1 cytotoxic (Tc1) profile, high numbers of CD8+ T-cell clones generated from HIV-seropositive individuals produced IL-4 in addition to IFN-gamma or IL-4 alone, thus showing a type 0 cytotoxic (Tc0)- or a type 2 cytotoxic (Tc2) profile, respectively. Tc0/Tc2 cells displayed lower cytolytic activity than Tc1 cells, including a reduced ability to lyse autologous targets pulsed with HIV or HIV peptides. By contrast, the production of chemokines RANTES and macrophage inflammatory protein-1alpha was comparable in Tc1, Tc0, and Tc2 clones irrespective of whether they were derived from HIV-seronegative or HIV-seropositive individuals. When CD8+ T-cell clones were generated from PBMC cultures of HIV-seronegative individuals conditioned with IL-4 plus an anti-IL-12 antibody (Ab), a shift towards the Tc0/Tc2-like profile was observed. Conversely, the addition to PBMC cultures of IL-12 plus an anti-IL-4 Ab shifted the differentiation of CD8+ T cells from HIV-infected individuals towards the Tc1-like profile, whereas IL-12 or anti-IL-4 Ab alone had a lower Tc1-promoting effect. Irradiated PBMC from HIV-infected individuals, used as feeder cells, shifted the differentiation of CD8+ T cells from a healthy HIV-seronegative individual towards the Tc0/Tc2-like profile. On the other hand, a shift towards the Tcl-like profile was noted in CD8+ T-cell clones generated from the skin specimens of two HIV-seropositive patients with Kaposi's sarcoma, successfully treated with IFN-alpha, in comparison to CD8+ clones generated from the same skin areas before treatment. The IFN-alpha-induced Tc1 shift could be prevented by the incubation of skin-infiltrating CD8+ T cells with IL-4 before cloning. Taken together, these data indicate that both defective production of IL-12 and abnormal IL-4 production in bulk PBMC populations of HIV-infected individuals may contribute to the development of high numbers of CD8+ T-cell clones showing a Tc0/Tc2-like phenotype and reduced cytolytic potential against HIV itself. They also suggest that the cytokine profile of CD8+ T-cell clones can be modulated by cytokines (or anticytokine Ab) both in vitro and in vivo.
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PMID:Functional characterization and modulation of cytokine production by CD8+ T cells from human immunodeficiency virus-infected individuals. 916 Jun 72

There is a close correspondence between the ability of RANTES and macrophage inflammatory proteins 1alpha and 1beta to activate CC chemokine receptor 5 (CCR5) and the ability to inhibit CCR5-dependent membrane fusion mediated by the envelope glycoprotein of human immunodeficiency virus (HIV), type 1. This finding suggests that some of the structural determinants for CC chemokine/CCR5 interactions and CCR5 HIV-1 fusion co-receptor activity may be shared. Recent studies using human CCR5/CCR2B chimeras have suggested that the determinants of CCR5 co-receptor activity are complex and may involve multiple extracellular receptor domains and that viral co-receptor activity is dissociable from ligand-dependent signaling responses. However, conclusive evidence demonstrating an important role for the second and third extracellular regions of human CCR5 is lacking. Furthermore, to determine whether the determinants for CCR5 co-receptor activity overlap with those required for agonist activity, studies that compare the chemokine specificity for inhibition of envelope-mediated cell fusion and the agonist profile of chimeric receptors are necessary. In the present report, using a series of CCR5/CCR2B chimeras we ascribe an important role for the second and third extracellular loop of CCR5 in supporting the co-receptor activity of CCR5. We also provide evidence that the intracytoplasmic tail of CCR5 does not play an important role in supporting HIV-1 entry. The hypothesis that the structural determinants for CC chemokine/CCR5 interactions and CCR5 HIV-1 fusion co-receptor activity may be shared was confirmed by two novel observations: first, the fusion activity supported by two hybrid receptors could be inhibited by both RANTES and monocyte chemoattractant protein-1, chemokines specific to CCR5 and CCR2B, respectively; and second, the chemokine specificity for inhibition of envelope-mediated cell fusion matched the agonist profile of these hybrid receptors. These data shed new light on the structural determinants involved in these distinct activities of CCR5 and may have important implications for the development of CCR5-targeted anti-viral compounds.
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PMID:CC chemokine receptor 5-mediated signaling and HIV-1 Co-receptor activity share common structural determinants. Critical residues in the third extracellular loop support HIV-1 fusion. 924 36

Certain individuals with elevated levels of macrophage inflammatory protein (MIP)1 alpha, MIP1 beta and RANTES expression appear to be resistant to human immunodeficiency virus (HIV) infection. In this work, we demonstrate that chemokines production by peripheral blood mononuclear cells (PBMCs) are homeostatic parameters varying from one individual to another, and we define optimized experimental conditions to reproducibly assess these parameters. We also studied alpha- and gamma-interferons (IFN alpha and IFN gamma, respectively) which have been implicated in the pathogenesis of acquired immunodeficiency syndrome (AIDS). The kinetics of production of all these cytokines by fresh PBMCs were determined upon stimulation with phytohemagglutinin (PHA), staphylococcus enterotoxin b (SEB) and purified protein derivative (PPD). RANTES and MIP1 alpha are produced early in response to activation, followed by MIP1 beta, (alpha-interferon, gamma-interferon, alpha IFN, gamma-IFN alpha and IFN alpha and gamma. These results suggest that using our methodology, chemokines levels can be reliably determined, permitting the performance of accurate genetic studies using PBMCs from various cohorts (siblings or AIDS related cohorts).
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PMID:Homeostasis of chemokines, interferon production and lymphocyte subsets: implications for AIDS pathogenesis. 924 20

Blood dendritic cells (DC) are susceptible to both macrophage (M) and T-cell line (T) tropic human immunodeficiency virus type 1. The CC chemokines RANTES, macrophage inflammatory protein-1alpha (MIP-1alpha), MIP-1beta, eotaxin, and, to a lesser extent, monocyte chemoattractant protein-1 (MCP-1) and MCP-4 blocked entry of M-tropic virus into blood DC. The CXC chemokine, SDF-1, a fusin (CXCR4 chemokine receptor) ligand, and an antifusin antibody inhibited DC entry by T-tropic virus. Purified blood DC contained CCR1, CCR2, CCR3, and CCR5 as well as the CXCR4 chemokine receptor RNA transcripts and high levels of fusin on the cell surface. The coexpression of multiple chemokine receptors offers a molecular mechanism to explain the permissiveness of DC for both M- and T-tropic viruses.
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PMID:Human immunodeficiency virus-1 entry into purified blood dendritic cells through CC and CXC chemokine coreceptors. 926 54

Until recently, chimpanzees were considered susceptible to human immunodeficiency virus type 1 (HIV-1) infection, but refractory to disease induction based on the asymptomatic status of all experimentally infected chimpanzees after over 10 years postinfection (PI). However, a decline in peripheral CD4+ T cells was noted in one chimpanzee (C499) of the Yerkes cohort of HIV-1 infected apes, after 11 years PI concurrent with increasing plasma viral load. These clinical signs were followed by the occurrence of opportunistic infections, thrombocytopenia, and progressive anemia leading to euthanasia. A second chimpanzee (C455) was transfused with blood from C499 collected during the symptomatic stage. Shortly thereafter, this second animal showed a rapid decline in peripheral CD4+ T-cell levels and sustained high viral load. Hematological analyses showed a 50% decrease in CFU-GM for both apes during the symptomatic phase and a reduction of 40% and 73% of the total CFU despite normal levels of CD34+ cells in the bone marrow. Cryopreserved sequential PBMC samples from these two chimpanzees were analyzed for constitutive and PHA-P induced levels of cytokines and chemokines. Data show that whereas there were no detectable constitutive levels of mRNA coding for IL-2, 4, and 10, there appears to be a transient increase in IFN-gamma message level coincident with increased viremia and this IFN-gamma synthesis decreased with disease progression. PHA-induced cytokine mRNA analysis showed low or undetectable levels of IL-4 and IL-10 mRNA in all samples and a marked decrease in the levels of IL-2 shortly after HIV infection. In addition, there was also a gradual decrease in IFN-gamma mRNA with progression of disease. Of interest were the findings of high to normal levels of PHA-induced synthesis of the chemokines MIP-1alpha, MIP-1beta, and RANTES in samples during the asymptomatic and early symptomatic period, which also dramatically decreased at late stages of the disease. These data suggest important roles for IL-2, IFN-gamma, and the chemokines in the regulation of immune responses in HIV-1-infected chimpanzees.
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PMID:Immune and hematopoietic parameters in HIV-1-infected chimpanzees during clinical progression toward AIDS. 927 Nov 84

The human immunodeficiency virus type 1 was recently found to use several chemokine receptors in addition to the CD4 molecule for attachment to, and fusion with, CD4+ cells. The interaction between macrophage-tropic HIV-1 strains and one of these chemokine receptors, CCR5, was shown to involve the V3-loop of the viral envelope glycoprotein gp120. Physiological ligands of CCR5, namely the beta-chemokines MIP-1alpha, MIP-1beta, and RANTES, were found to competitively inhibit the V3-loop-CCR5 interaction. We therefore hypothesized that the V3-loop of gp120 of macrophage-tropic HIV-1 may share a binding site on CCR5 with MIP-1alpha, MIP-1beta, and RANTES and that the V3-loop therefore might have some homology with these beta-chemokines. In the present study, we could demonstrate that affinity purified anti-V3-loop antibodies isolated from serum of an HIV-1-infected patient bound to MIP-1alpha and RANTES. Furthermore, sera of HIV-infected hemophilia patients without AIDS or ARC had significantly higher anti-MIP-1alpha and anti-RANTES antibody activities than sera of HIV-infected hemophilia patients with AIDS. We speculate that the higher activities of anti-MIP-1alpha and anti-RANTES antibodies in asymptomatic HIV-1 infected individuals might be due to a cross-reaction of beta-chemokines with anti-V3-loop antibodies raised against gp120 of macrophage-tropic HIV-1 strains, known to be prevailing in the asymptomatic stage of HIV infection. Such anti-chemokine antibodies may play a deleterious role in the pathogenesis of AIDS by reducing the chemokines' potential to inhibit HIV-1 entry into CD4+ cells.
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PMID:Anti-MIP-1alpha and anti-RANTES antibodies: new allies of HIV-1? 928 93

The effects of the C-C chemokines RANTES (regulation upon activation normal T-cell expressed and secreted) and MCP-3 (monocyte chemotactic protein 3) on human immunodeficiency virus (HIV) replication in normal human peripheral blood mononuclear cells (PBMC) activated in vitro with phytohemagglutinin (PHA) were investigated. The following T-cell line-tropic (T-tropic) HIV strains were tested: HIV type 1 (HIV-1) SF-2, HIV-1 IIIB, HIV-1 MN, HIV-1 NDK, HIV-1 HE, HIV-1 NL4-3, HIV-2 ROD, and HIV-2 EHO. The strain most sensitive to the antiviral effects of RANTES and MCP-3 appeared to be HIV-1 SF-2. A 50% inhibitory concentration for HIV-1 SF-2 of 4 ng of RANTES per ml was obtained, and that of MCP-3 was about 1 ng/ml. However, MCP-3 was inactive at 100 ng/ml. Other HIV-1 strains, such as MN and HE, were less sensitive to the antiviral effects of RANTES and MCP-3, whereas all the other HIV strains tested were insensitive. Although the ratio of CD3+ CD4+ to CD3+ CD8+ T cells was the same in HIV-infected PBMC cultures treated or untreated with the chemokines, RANTES and MCP-3 interfered with the binding of monoclonal antibody (MAb) OKT4 to the CD4 receptor on T cells but not with the binding of MAb OKT4A. Therefore, RANTES and MCP-3 not only interfere with the HIV-induced fusion process but also have some modulating effect on the CD4 cell receptor. The chemokines did not affect HIV-1 binding to PHA-stimulated PBMC. Taken together, our observations point to the important role that both RANTES and MCP-3 may play in inhibiting HIV-1 replication of certain T-tropic strains in primary PBMC cultures. This may have important implications for immunotherapeutic strategies designed to slow down disease progression in AIDS.
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PMID:RANTES and MCP-3 inhibit the replication of T-cell-tropic human immunodeficiency virus type 1 strains (SF-2, MN, and HE). 931 6

Unique among known human herpesviruses, Kaposi's sarcoma-associated herpesvirus (KSHV or HHV-8) encodes chemokine-like proteins (vMIP-I and vMIP-II). vMIP-II was shown to block infection of human immunodeficiency virus-type 1 (HIV-1) on a CD4-positive cell line expressing CCR3 and to a lesser extent on one expressing CCR5, whereas both vMIP-I and vMIP-II partially inhibited HIV infection of peripheral blood mononuclear cells. Like eotaxin, vMIP-II activated and chemoattracted human eosinophils by way of CCR3. vMIP-I and vMIP-II, but not cellular MIP-1alpha or RANTES, were highly angiogenic in the chorioallantoic assay, suggesting a possible pathogenic role in Kaposi's sarcoma.
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PMID:Angiogenic and HIV-inhibitory functions of KSHV-encoded chemokines. 957 77

CCR5, a receptor for the CC chemokines RANTES, Mip1alpha, and Mip1beta, has been identified as a coreceptor for infections by macrophage-tropic isolates of human immunodeficiency virus type 1 (HIV-1). To study its structure and function, we isolated cDNA clones of human, African green monkey (AGM), and NIH/Swiss mouse CCR5s, and we quantitatively analyzed infections by macrophage-tropic HIV-1 and SIVmac251 after transfecting human HeLa-CD4 cells with the CCR5 expression vectors. The AGM and NIH/Swiss mouse CCR5 proteins are 97.7 to 98.3% and 79.8% identical to the human protein, respectively. In addition, we analyzed site-directed mutants and chimeras of these CCR5s. Cell surface expression of CCR5 proteins was monitored by using a specific rabbit antiserum and by binding the chemokine [125I]Mip1beta. Our major results were as follows. (i) Two distinct AGM CCR5 sequences were reproducibly found in DNA from CV-1 cells. The AGM clone 1 CCR5 protein differs from that of clone 2 by two substitutions, Y14N in the amino-terminal extracellular region and L352F at the carboxyl terminus. Interestingly, AGM clone 1 CCR5 was inactive as a coreceptor for all tested macrophage-tropic isolates of HIV-1, whereas AGM clone 2 CCR5 was active. As shown by chimera studies and site-directed mutagenesis, the Y14N substitution in AGM clone 1 CCR5 was solely responsible for blocking HIV-1 infections. In contrast, both AGM CCR5 clones were active coreceptors for SIVmac251. Studies of DNA samples from other AGMs indicated frequent additional CCR5 polymorphisms, and we cloned an AGM clone 2 variant with a Q93R substitution in the extracellular loop 1 from one heterozygote. This variant CCR5 was active as a coreceptor for SIVmac251 but was only weakly active for macrophage-tropic isolates of HIV-1. In addition, SIVmac251 appeared to be dependent on the extracellular amino terminus and loop 2 regions of human CCR5 for maximal infection. Our results suggest major differences in the interactions of SIVmac251 and macrophage-tropic HIV-1 isolates with 19, N13, and Y14 in the amino terminus; with Q93 in extracellular loop 1; and with extracellular loop 2 of human CCR5. (ii) The NIH/Swiss mouse CCR5 protein differs at multiple positions from sequences recently reported for other inbred strains of mice. This CCR5 was inactive as a coreceptor for HIV-1 and SIVmac251. Studies of chimeras that contained different portions of NIH/Swiss mouse CCR5 substituted into human CCR5, as well as the reciprocal chimeras, indicated that the amino-terminal region and extracellular loops 1 and 2 of human CCR5 contribute to its coreceptor activity for macrophage-tropic isolates of HIV-1. Specific differences with previous CCR5 chimera results occurred because the NIH/Swiss mouse CCR5 contains a unique substitution corresponding to P183L in extracellular loop 2 that is nonpermissive for coreceptor activity. We conclude that diverse CCR5 sequences occur in AGMs and mice, that SIVmac251 and macrophage-tropic HIV-1 isolates interact differently with specific CCR5 amino acids, and that multiple regions of human CCR5 contribute to its coreceptor functions. In addition, we have identified naturally occurring amino acid polymorphisms in three extracellular regions of CCR5 (Y14N, Q93R, and P183L) that do not interfere with cell surface expression or Mip1beta binding but prevent infections by macrophage-tropic isolates of HIV-1. In contrast to previous evidence, these results suggest that CCR5 contains critical sites that are essential for HIV-1 infections.
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PMID:Polymorphisms in the CCR5 genes of African green monkeys and mice implicate specific amino acids in infections by simian and human immunodeficiency viruses. 934 22

Following the identification of the C-C chemokines RANTES, MIP-1alpha and MIP-1beta as major human immunodeficiency virus (HIV)-suppressive factors produced by CD8+ T cells, several chemokine receptors were found to serve as membrane co-receptors for primate immunodeficiency lentiretroviruses. The two most widely used co-receptors thus far recognized, CCR5 and CXCR4, are expressed by both activated T lymphocytes and mononuclear phagocytes. CCR5, a specific RANTES, MIP-1alpha and MIP-1 receptor, is used preferentially by non-MT2-tropic HIV-1 and HIV-2 strains and by simian immunodeficiency virus (SIV), whereas CXCR4, a receptor for the C-X-C chemokine SDF-1, is used by MT2-tropic HIV-1 and HIV-2, but not by SIV. Other receptors with a more restricted cellular distribution, such as CCR2b, CCR3 and STRL33, can also function as co-receptors for selected viral isolates. The third variable region (V3) of the gp120 envelope glycoprotein of HIV-1 has been fingered as a critical determinant of the co-receptor choice. Here, we document a consistent pattern of evolution of viral co-receptor usage and sensitivity to chemokine-mediated suppression in a longitudinal follow-up of children with progressive HIV-1 infection. Viral isolates obtained during the asymptomatic stages generally used only CCR5 as a co-receptor and were inhibited by RANTES, MIP-1alpha and MIP-1beta, but not by SDF-1. By contrast, the majority of the isolates derived after the progression of the disease were resistant to C-C chemokines, having acquired the ability to use CXCR4 and, in some cases, CCR3, while gradually losing CCR5 usage. Surprisingly, most of these isolates were also insensitive to SDF-1, even when used in combination with RANTES. An early acquisition of CXCR4 usage predicted a poor prognosis. In children who progressed to AIDS without a shift to CXCR4 usage, all the sequential isolates were CCR5-dependent but showed a reduced sensitivity to C-C chemokines. Discrete changes in the V3 domain of gp120 were associated with the loss of sensitivity to C-C chemokines and the shift in co-receptor usage. These results suggest an adaptive evolution of HIV-1 in vivo, leading to escape from the control of the antiviral C-C chemokines.
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PMID:In vivo evolution of HIV-1 co-receptor usage and sensitivity to chemokine-mediated suppression. 935 2


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