Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Human herpesvirus type 8 vMIP-II has one of the broadest ranges of chemokine receptor binding and therefore a multiplicity of biologic effects, both immunologic and antiviral. These properties make vMIP-II an attractive effector gene to be expressed from gene therapy vectors. The present studies were concerned with both therapeutic approaches: (1) an anti-simian immunodeficiency virus (SIV) biologic, and (2) an effector gene in SIV-based vectors. Regarding its antiviral properties, vMIP-II expressed from bacteria and SIV-based vectors bound the surface of CEMx174 cells and specifically suppressed SIVmac251 infection. A CCR3 monoclonal antibody partially inhibited vMIP-II binding, suggesting that both SIVmac251 and vMIP-II utilize a similar CCR3-like receptor for CEMx174 cell binding. Replication competent SIV-based vectors containing forward and reverse vMIP-II produced neither identifiable vMIP-II nor virions for the first 21 days. Virus replication occurred after this period. Significant sequence alterations in the forward vMIP-II containing replication competent vector transcripts were responsible for the failure of vMIP-II expression. The genetic basis for the initial failure to replicate virus and its later restoration was not determined but appeared in the II-PIMv containing vectors to coincide with deletions and compensatory rearrangements in nef 3' of the polypurine tract. Cells transfected with SIVmac239Delta3DeltaLTR-vMIP-II vectors expressed biologically active vMIP-II that bound CEMx174 cells and suppressed SIVmac251 infection. These data suggest that replication defective SIV vectors expressing immunobiolgic genes such as vMIP-II may prove useful in gene therapies, particularly in augmenting immune responses in chronically infected individuals.
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PMID:The effects of HHV-8 vMIP-II on SIVmac251 infection and replication competent and incompetent SIVmac239Delta3 vectors. 1290 39

Entry of human immunodeficiency type 1 virus (HIV-1) into target cells requires both CD(4)and one of the chemokine receptors. Viruses predominantly use one, or occasionally both, of the major co-receptors CCR5 and CXCR4, although other receptors, including CCR2B and CCR3, function as minor co-receptors. A 32-nucleotide deletion (D32) within the b-chemokine receptor 5 gene (CCR5) has been described in subjects who remain uninfected despite extensive exposition to HIV-1. The heterozygous genotype delays disease progression. This allele is common among Caucasians, but has not been found in people of African or Asian ancestry. A more common transition involving a valine to isoleucine switch in transmembrane domain I of CCR2B (64I), with unknown functional consequences, was found to delay disease progression but not to reduce infection risk. As the Brazilian population consists of a mixture of several ethnic groups, we decided to examine the genotype frequency of these polymorphisms in this country. There were 11.5% CCR5 heterozygotes among the HIV-1 infected population and 12.5% among uninfected individuals, similar to data from North America and Western Europe. The prevalence of CCR2-64I homozygotes and heterozygotes was 0.06 and 15.2%, respectively, also similar to what is known for North America and Western Europe.
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PMID:Frequency of polymorphisms of genes coding for HIV-1 co-receptors CCR5 and CCR2 in a Brazilian population. 1453 83

The genetic evolution of human immunodeficiency virus type 1 (HIV-1) in the brain is distinct from that in lymphoid tissues, indicating tissue-specific compartmentalization of the virus. Few primary HIV-1 envelope glycoproteins (Envs) from uncultured brain tissues have been biologically well characterized. In this study, we analyzed 37 full-length env genes from uncultured brain biopsy and blood samples from four patients with AIDS. Phylogenetic analysis of intrapatient sequence sets showed distinct clustering of brain relative to blood env sequences. However, no brain-specific signature sequence was identified. Furthermore, there was no significant difference in the number or positions of N-linked glycosylation sites between brain and blood env sequences. The patterns of coreceptor usage were heterogeneous, with no clear distinction between brain and blood env clones. Nine Envs used CCR5 as a coreceptor, one used CXCR4, and two used both CCR5 and CXCR4 in cell-to-cell fusion assays. Eight Envs could also use CCR3, CCR8, GPR15, STRL33, Apj, and/or GPR1, but these coreceptors did not play a major role in virus entry into microglia. Recognition of epitopes by the 2F5, T30, AG10H9, F105, 17b, and C11 monoclonal antibodies varied among env clones, reflecting genetic and conformational heterogeneity. Envs from two patients contained 28 to 32 N-glycosylation sites in gp120, compared to around 25 in lab strains and well-characterized primary isolates. These results suggest that HIV-1 Envs in brain cannot be distinguished from those in blood on the basis of coreceptor usage or the number or positions of N-glycosylation sites, indicating that other properties underlie neurotropism. The study also demonstrates characteristics of primary HIV-1 Envs from uncultured tissues and implies that Env variants that are glycosylated more extensively than lab strains and well-characterized primary isolates should be considered during development of vaccines and neutralizing antibodies.
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PMID:Genetic and functional analysis of full-length human immunodeficiency virus type 1 env genes derived from brain and blood of patients with AIDS. 1458 70

In order to test the hypothesis that alteration of cell cycle proteins are involved in the neuronal damage caused by human immunodeficiency virus (HIV), the authors have been studying the effect of chemokines on the CDK/Rb/E2F-1 pathway--which is involved in neuronal apoptosis and differentiation. First, they have asked whether CXCR4, the specific receptor for the chemokine SDF-1 and X4-using gp120s, can regulate Rb and E2F-1 activity in cultures of differentiated rat neurons. Although CCR3 and CCR5 are known to mediate infection of microglia by HIV-1, recent evidence indicate that CXCR4 also play important roles in HIV-induced neuronal injury, and dual-tropic isolates that use CXCR4 to infect macrophages have recently been reported. The authors have focused on two specific brain areas in which CXCR4 is physiologically relevant, i.e., the cerebellum and the hippocampus. So far, the data indicate that changes in the nuclear and cytosolic levels of Rb, which result in the functional loss of this protein, are associated with apoptosis in these neurons, and that SDF-1alpha and gp120IIIB affect this pathway. A summary of the findings are presented.
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PMID:Regulation of cell cycle proteins by chemokine receptors: A novel pathway in human immunodeficiency virus neuropathogenesis? 1498 48

The idea that opioids modulate the immune system is not new. By the late 19th century, Cantacuzene, used morphine to suppress cellular immunity and lower the resistance of guinea pigs to bacterial infection. While exogenous opioids mediate immunosuppression, endogenous opiates exert opposite actions. Acute and chronic opioid administration is known to have inhibitory effects on humoral and cellular immune responses including antibody production, natural killer cell activity, cytokine expression, and phagocytic activity. Opiates behave like cytokines, modulating the immune response by interaction with their receptors in the central nervous system and in the periphery. Potential mechanisms by which central opiates modulate peripheral immune functions may involve both the hypothalamic-pituitary-adrenal axis and the autonomic nervous system. The presence of opioid receptors outside the central nervous system is increasingly recognized. Those receptors have been identified not only in peripheral nerves but also in immune inflammatory cells. The immunosuppression mediated by opiates may explain the increased incidence of infection in heroin addicts. Opiates may also promote immunodeficiency virus infection by decreasing the secretion of alpha and beta chemokines (important inhibitory cytokines for the expression of HIV) and at the same time increasing the expression of chemoreceptors CCR5 and CCR3, coreceptors for the virus. The fact that peripheral immunosupression is mediated at least in part by opioid receptors located in the central nervous system and that intrathecally administered opioids do not exert the same immunosuppressive effects may have important clinical implications for those patients receiving long-term opioid therapy for malignant and nonmalignant pain.
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PMID:Opioid therapy and immunosuppression: a review. 1535 31

Here we report that the N-pyridinylmethyl cyclam analog AMD3451 has antiviral activity against a wide variety of R5, R5/X4, and X4 strains of human immunodeficiency virus type 1 (HIV-1) and HIV-2 (50% inhibitory concentration [IC(50)] ranging from 1.2 to 26.5 microM) in various T-cell lines, CCR5- or CXCR4-transfected cells, peripheral blood mononuclear cells (PBMCs), and monocytes/macrophages. AMD3451 also inhibited R5, R5/X4, and X4 HIV-1 primary clinical isolates in PBMCs (IC(50), 1.8 to 7.3 microM). A PCR-based viral entry assay revealed that AMD3451 blocks R5 and X4 HIV-1 infection at the virus entry stage. AMD3451 dose-dependently inhibited the intracellular Ca(2+) signaling induced by the CXCR4 ligand CXCL12 in T-lymphocytic cells and in CXCR4-transfected cells, as well as the Ca(2+) flux induced by the CCR5 ligands CCL5, CCL3, and CCL4 in CCR5-transfected cells. The compound did not interfere with chemokine-induced Ca(2+) signaling through CCR1, CCR2, CCR3, CCR4, CCR6, CCR9, or CXCR3 and did not induce intracellular Ca(2+) signaling by itself at concentrations up to 400 microM. In freshly isolated monocytes, AMD3451 inhibited the Ca(2+) flux induced by CXCL12 and CCL4 but not that induced by CCL2, CCL3, CCL5, and CCL7. The CXCL12- and CCL3-induced chemotaxis was also dose-dependently inhibited by AMD3451. Furthermore, AMD3451 inhibited CXCL12- and CCL3L1-induced endocytosis in CXCR4- and CCR5-transfected cells. AMD3451, in contrast to the specific CXCR4 antagonist AMD3100, did not inhibit but enhanced the binding of several anti-CXCR4 monoclonal antibodies (such as clone 12G5) at the cell surface, pointing to a different interaction with CXCR4. AMD3451 is the first low-molecular-weight anti-HIV agent with selective HIV coreceptor, CCR5 and CXCR4, interaction.
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PMID:Inhibition of human immunodeficiency virus replication by a dual CCR5/CXCR4 antagonist. 1554 51

To dissect the haplotype structure of candidate genes for disease association studies, it is important to understand the nature of genetic variation at these loci in different populations. We present a survey of haplotype structure and linkage disequilibrium of chemokine and chemokine receptor genes in 11 geographically-distinct population samples (n=728). Chemokine proteins are involved in intercellular signalling and the immune response. These molecules are important modulators of human immunodeficiency virus (HIV)-1 infection and the progression of the acquired immune deficiency syndrome, tumour development and the metastatic process of cancer. To study the extent of genetic variation in this gene family, single nucleotide polymorphisms (SNPs) from 13 chemokine and chemokine receptor genes were genotyped using the 5' nuclease assay (TaqMan). SNP haplotypes, estimated from unphased genotypes using the Expectation-Maximization-algorithm, are described in a cluster of four CC-chemokine receptor genes (CCR3, CCR2, CCR5 and CCRL2) on chromosome 3p21, and a cluster of three CC-chemokine genes [MPIF-1 (CCL23), PARC (CCL18) and MIP-1alpha (CCL3)] on chromosome 17q11-12. The 32 base pair (bp) deletion in exon 4 of CCR5 was also included in the haplotype analysis of 3p21. A total of 87.5 per cent of the variation of 14 biallelic loci scattered over 150 kilobases of 3p21 is explained by 11 haplotypes which have a frequency of at least 1 per cent in the total sample. An analysis of haplotype blocks in this region indicates recombination between CCR2 and CCR5, although long-range pairwise linkage disequilibrium across the region appears to remain intact on two common haplotypes. A reduced-median network demonstrates a clear relationship between 3p21 haplotypes, rooted by the putative ancestral haplotype determined by direct sequencing of four primate species. Analysis of six SNPs on 17q11-12 indicates that 97.5 per cent of the variation is explained by 15 haplotypes, representing at least 1 per cent of the total sample. Additionally, a possible signature of selection at a non-synonymous coding SNP (M106V) in the MPIF-1 (CCL23) gene warrants further study. We anticipate that the results of this study of chemokine and chemokine receptor variation will be applicable to more extensive surveys of long-range haplotype structure in these gene regions and to association studies of HIV-1 disease and cancer.
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PMID:Haplotype structure and linkage disequilibrium in chemokine and chemokine receptor genes. 1558 86

HIV-1 affects microglia and astroglia, which subsequently contributes to the neurodegenerative changes. Viral proteins cause neurotoxicity by direct action on the CNS cells or by activating glial cells to cause the release of cytokines, chemokines or neurotoxic substances. Opioid abuse has been postulated as a cofactor in the immunopathogenesis of human immunodeficiency virus (HIV) infection and AIDS. HIV-induced pathogenesis is exacerbated by opiate abuse and that the synergistic neurotoxicity is a direct effect of opiates on the CNS. Chemokines and their receptors have been implicated in the pathogenesis of neuroAIDS. Herein we describe the effects of morphine and/or gp120 on the expression of the genes for the beta-chemokine MIP-1beta and its receptors CCR3 and CCR5 by the U373 cells which are a human brain-derived astrocytoma/glioblastoma cell line. Our results indicate that treatment of U373 cells with morphine significantly downregulated the gene expression of the beta chemokine, MIP-1 beta, while reciprocally upregulating the expression of its specific receptors, CCR3 and CCR5 suggesting that the capacity of mu-opioids to increase HIV-1 co-receptor expression may promote viral binding, trafficking of HIV-1-infected cells, and enhanced disease progression. Additionally, opiates can enhance the cytotoxicity of HIV-1 viral protein gp120 via mechanisms that involve intracellular calcium modulation resulting in direct actions on astroglia, making them an important cellular target for HIV-opiate interactions.
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PMID:Morphine exacerbates HIV-1 viral protein gp120 induced modulation of chemokine gene expression in U373 astrocytoma cells. 1602 59

Highly active anti-retroviral therapy (HAART) has been very effective in reducing viral loads in human immunodeficiency virus (HIV)-1 patients. However, current therapies carry detrimental side effects, require complex drug regimes and are threatened by the emergence of drug-resistant variants. There is an urgent need for new anti-HIV drugs that target different stages of the replication cycle. Several synthetic small organic molecules that inhibit HIV infection by binding to the CCR5 coreceptor without causing cell activation have already been reported. Here, we have exploited a series of CCR5 antagonists to investigate their effects on diverse HIV and the simian counterpart (SIV) isolates for infection of a variety of cell types via different concentrations of cell surface CCR5. These inhibitors show no cross-reactivity against alternative HIV coreceptors including CCR3, CCR8, GPR1, APJ, CXCR4 and CXCR6. They are able to inhibit a diverse range of R5 and R5X4 HIV-1 isolates as well as HIV-2 and SIV strains. Inhibition was observed in cell lines as well as primary PBMCs and macrophages. The extent of inhibition was dependent on cell type and on cell surface CCR5 concentration. Our results underscore the potential of CCR5 inhibitors for clinical development.
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PMID:Inhibition of CCR5-mediated infection by diverse R5 and R5X4 HIV and SIV isolates using novel small molecule inhibitors of CCR5: effects of viral diversity, target cell and receptor density. 1615 92

The chemokine receptor genes of the CCR cluster on human chromosome 3p21 play important roles in humoral and cellular immune responses. Several of these receptors have been shown to influence human immunodeficiency virus infection and progression to AIDS, and their homologues may play a role in feline immunodeficiency virus infection. We report the isolation and sequencing of a 150-kb domestic cat BAC clone containing the feline CCR genes CCR1, CCR2, CCR3, and CCR5 to further analyze these four receptor genes within the family Felidae. Comparative and phylogenetic analyses reveal evidence for historic gene conversion between the adjacent CCR2 and CCR5 genes in the Felidae and in three independent mammalian orders (Primates, Cetartiodactyla, and Rodentia), resulting in higher than expected levels of sequence similarity between the two paralogous genes within each order. The gene conversion was restricted to the structural (transmembrane) domains of the CCR2 and CCR5 genes. We also discovered a recent gene conversion event between the third extracellular loop of CCR2 and CCR5 genes that was fixed in Asian lions and found at low frequency in African lions (Panthera leo), suggesting that this domain may have an important functional role. Our results suggest that ongoing parallel gene conversion between CCR2 and CCR5 promotes receptor heterodimerization in independent evolutionary lineages and offers an effective adaptive strategy for gene editing and coevolution among interactive immune response genes in mammals.
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PMID:Gene conversion between mammalian CCR2 and CCR5 chemokine receptor genes: a potential mechanism for receptor dimerization. 1754 54


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