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

Homozygosity for a variant of a chemokine receptor gene (CCR5) has been shown to protect from HIV-1 infection. Variants of the mannose-binding lectin (MBL) gene have been suggested to predispose to HIV-1 infection. These genetic variants and their possible role in susceptibility to HIV-1 infection were studied in sample material from more than 300 Finnish HIV-infected and control individuals. The genotyping was carried out efficiently using a novel, primer extension assay in a miniaturized oligonucleotide array format. Homozygotes for the protective deletion allele of the CCR5 gene were found only in the control group, and the frequency of the allele was high in the Finnish population. Homozygosity for the MBL variant alleles was enriched significantly in the HIV-1-infected group, thus providing further evidence for the harmfulness of MBL variant homozygosity in HIV-1 transmission.
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PMID:Contribution of the CCR5 and MBL genes to susceptibility to HIV type 1 infection in the Finnish population. 961 82

The role of host genes in the course of HIV-1 infection has been examined in different populations and among all major risk groups. Two extended human lymphocyte antigen (HLA) haplotypes, HLA A1-Cw7-B8-DR3-DQ2 and HLA A11-Cw4-B35-DR1-DQ1, are found to be associated with a faster progression to AIDS. The complement C4 factor and tumor necrosis factor genes of the major histocompatibility complex, as well as the mannose binding protein gene, have also been suggested to influence the outcome of AIDS. The recent discovery that chemokine receptors could serve as cofactors for HIV-1 cell entry has prompted a search for polymorphisms in chemokine receptor genes. A 32 base pair inactivating deletion in the CCR5 gene and a point mutation within the CCR2b gene resulting in a conservative amino acid substitution have been examined and shown to be independently associated with delayed disease progression. Together, these observations strongly support a genetic component in AIDS pathogenesis. This article synthesizes the current state of knowledge about the influence of host genes on HIV-1 disease progression. It provides a summary of all significant association studies reported so far. The role of the allelic polymorphism in these genes is discussed with regard to the immunopathogenesis of AIDS.
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PMID:Influence of host genes on HIV-1 disease progression. 961 42

The molecularly cloned viruses known as SIVmac239/R17Y and SIVmac239/YEnef cause extensive lymphocyte activation and induce an acute disease syndrome in macaque monkeys. One manifestation of this syndrome is a severe diffuse cutaneous maculopapular exanthem that is similar to the exanthem associated with HIV-1 infection. To examine the pathogenesis of this exanthem, biopsies obtained throughout the course of clinically evident rash were examined for the presence of virus by in situ hybridization and immunohistochemistry, and the cellular infiltrate was characterized with respect to cellular immunophenotype and chemokine receptor expression. The onset of rash was associated with abundant simian immunodeficiency virus nucleic acid and protein within perivascular dermal infiltrates and occasionally within intraepithelial cells. Analysis of cellular infiltrates showed that biopsies, obtained on the day of rash onset, were composed of equal numbers of CD4+ and CD8+ lymphocytes and abundant alphaEbeta7 positive cells surrounding vessels with upregulated endothelial E-selectin. Moreover, by examining virus expression in sequential skin biopsies from the same animal, the clearance of virus and the resolution of rash were associated with an increase in the percentage of cells expressing CD8, the chemokine receptor CXCR3, and GMP-17, a marker of cytotoxic granules. These results suggest that activated cytotoxic T cells are trafficking to sites of inflammation in the skin and directly or indirectly affect levels of viral replication at these sites.
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PMID:Characterization of the cutaneous exanthem in macaques infected with a Nef gene variant of SIVmac239. 962 Feb 96

Several members of the seven-transmembrane chemokine receptor family have been shown to serve, with CD4, as coreceptors for entry by human immunodeficiency virus type 1 (HIV-1). While coreceptor usage by HIV-1 primary isolates has been studied by several groups, there is only limited information available concerning coreceptor usage by primary HIV-2 isolates. In this study, we have analyzed coreceptor usage of 15 primary HIV-2 isolates, using lymphocytes from a donor with nonfunctional CCR5 (CCR5 -/-; homozygous 32-bp deletion). Based on the infections of PBMCs, seven of these primary isolates had an absolute requirement for CCR5 expression, whereas the remaining eight exhibited a broader coreceptor usage. All CCR5-requiring isolates were non-syncytium inducing, whereas isolates utilizing multiple coreceptors were syncytium inducing. Blocking experiments using known ligands for chemokine receptors provided indirect evidence for additional coreceptor utilization by primary HIV-2 isolates. Analysis of GHOST4 cell lines expressing various chemokine receptors (CCR1, CCR2b, CCR3, CCR4, CCR5, CXCR4, BONZO, and BOB) further defined specific coreceptor usage of primary HIV-2 isolates. The receptors used included CXCR4, CCR1-5, and the recently described receptors BONZO and BOB. However, the efficiency at which the coreceptors were utilized varied greatly among the various isolates. Analysis of V3 envelope sequences revealed no specific motif that correlated with coreceptor usage. Our data demonstrate that primary HIV-2 isolates are capable of using a broad range of coreceptors for productive infection in vitro. Additionally, our data suggest that expanded coreceptor usage by HIV-2 may correlate with disease progression.
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PMID:Genetically divergent strains of human immunodeficiency virus type 2 use multiple coreceptors for viral entry. 962 Sep 97

To evaluate the feasibility of using transgenic rabbits expressing CCR5 and CD4 as a small-animal model of human immunodeficiency virus type 1 (HIV) disease, we examined whether the expression of the human chemokine receptor (CCR5) and human CD4 would render a rabbit cell line (SIRC) permissive to HIV replication. Histologically, SIRC cells expressing CD4 and CCR5 formed multinucleated cells (syncytia) upon exposure to BaL, a macrophagetropic strain of HIV that uses CCR5 for cell entry. Intracellular viral capsid p24 staining showed abundant viral gene expression in BaL-infected SIRC cells expressing CD4 and CCR5. In contrast, neither SIRC cells expressing CD4 alone nor murine 3T3 cells expressing CCR5 and CD4 exhibited significant expression of p24. These stably transfected rabbit cells were also highly permissive for the production of virions upon infection by two other CCR5-dependent strains (JR-CSF and YU-2) but not by a CXCR4-dependent strain (NL4-3). The functional integrity of these virions was demonstrated by the successful infection of human peripheral blood mononuclear cells (PBMC) with viral stocks prepared from these transfected rabbit cells. Furthermore, primary rabbit PBMC were found to be permissive for production of infectious virions after circumventing the cellular entry step. These results suggest that a transgenic rabbit model for the study of HIV disease may be feasible.
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PMID:Rabbit cells expressing human CD4 and human CCR5 are highly permissive for human immunodeficiency virus type 1 infection. 962 Oct 31

Individuals who are homozygous for the 32-bp deletion in the gene coding for the chemokine receptor and major human immunodeficiency virus type 1 (HIV-1) coreceptor CCR5 (CCR5 -/-) lack functional cell surface CCR5 molecules and are relatively resistant to HIV-1 infection. HIV-1 infection in CCR5 -/- individuals, although rare, has been increasingly documented. We now report that the viral quasispecies from one such individual throughout disease is homogenous, T cell line tropic, and phenotypically syncytium inducing (SI); exclusively uses CXCR4; and replicates well in CCR5 -/- primary T cells. The recently discovered coreceptors BOB and Bonzo are not used. Although early and persistent SI variants have been described in longitudinal studies, this is the first demonstration of exclusive and persistent CXCR4 usage. With the caveat that the earliest viruses available from this subject were from approximately 4 years following primary infection, these data suggest that HIV-1 infection can be mediated and persistently maintained by viruses which exclusively utilize CXCR4. The lack of evolution toward the available minor coreceptors in this subject underscores the dominant biological roles of the major coreceptors CCR5 and CXCR4. This and two similar subjects (R. Biti, R. Ffrench, J. Young, B. Bennetts, G. Stewart, and T. Liang, Nat. Med. 3:252-253, 1997; I. Theodoreu, L. Meyer, M. Magierowska, C. Katlama, and C. Rouzioux, Lancet 349:1219-1220, 1997) showed relatively rapid CD4+ T-cell declines despite average or low initial viral RNA load. Since viruses which use CXCR4 exclusively cannot infect macrophages, these data have implications for the relative infection of the T-cell compartment versus the macrophage compartment in vivo and for the development of CCR5-based therapeutics.
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PMID:Exclusive and persistent use of the entry coreceptor CXCR4 by human immunodeficiency virus type 1 from a subject homozygous for CCR5 delta32. 962 Oct 67

Chemokines and their receptors are important in cell migration during inflammation, in the establishment of functional lymphoid microenvironments, and in organogenesis. The chemokine receptor CXCR4 is broadly expressed in cells of both the immune and the central nervous systems and can mediate migration of resting leukocytes and haematopoietic progenitors in response to its ligand, SDF-1. CXCR4 is also a major receptor for strains of human immunodeficiency virus-1 (HIV-1) that arise during progression to immunodeficiency and AIDS dementia. Here we show that mice lacking CXCR4 exhibit haematopoietic and cardiac defects identical to those of SDF-1-deficient mice, indicating that CXCR4 may be the only receptor for SDF-1. Furthermore, fetal cerebellar development in mutant animals is markedly different from that in wild-type animals, with many proliferating granule cells invading the cerebellar anlage. This is, to our knowledge, the first demonstration of the involvement of a G-protein-coupled chemokine receptor in neuronal cell migration and patterning in the central nervous system. These results may be important for designing strategies to block HIV entry into cells and for understanding mechanisms of pathogenesis in AIDS dementia.
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PMID:Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development. 963 28

The human immunodeficiency virus HIV-1 establishes persistent infections in humans which lead to acquired immunodeficiency syndrome (AIDS). The HIV-1 envelope glycoproteins, gp120 and gp41, are assembled into a trimeric complex that mediates virus entry into target cells. HIV-1 entry depends on the sequential interaction of the gp120 exterior envelope glycoprotein with the receptors on the cell, CD4 and members of the chemokine receptor family. The gp120 glycoprotein, which can be shed from the envelope complex, elicits both virus-neutralizing and non-neutralizing antibodies during natural infection. Antibodies that lack neutralizing activity are often directed against the gp120 regions that are occluded on the assembled trimer and which are exposed only upon shedding. Neutralizing antibodies, by contrast, must access the functional envelope glycoprotein complex and typically recognize conserved or variable epitopes near the receptor-binding regions. Here we describe the spatial organization of conserved neutralization epitopes on gp120, using epitope maps in conjunction with the X-ray crystal structure of a ternary complex that includes a gp120 core, CD4 and a neutralizing antibody. A large fraction of the predicted accessible surface of gp120 in the trimer is composed of variable, heavily glycosylated core and loop structures that surround the receptor-binding regions. Understanding the structural basis for the ability of HIV-1 to evade the humoral immune response should assist in the design of a vaccine.
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PMID:The antigenic structure of the HIV gp120 envelope glycoprotein. 964 73

HIV infection is associated with both a hyperactivity of the immune system and decreased immune responses against specific antigens. A similar pattern is observed when considering cytokine production in HIV-infected patients. Several cytokines are spontaneously produced at an increased level, whereas other cytokines playing an important role during cell-mediated immune responses are produced at a low level following stimulation. This deregulation of cytokine production may participate to the immune deficiency, both by impairing immune responses and by accelerating CD4+ T lymphocyte destruction. Chemokine receptors have recently been shown to function as coreceptors for the virus, and to govern its cellular tropism. Heterogeneous expression of chemokine receptor may contribute to differences in infectability as well as in rate of progression of the disease between individuals. Better understanding of the role of cytokines and chemokines in HIV infection suggests new therapeutic approaches where administration of cytokines or cytokine antagonists may allow the immune system to function in better conditions, to stimulate antiviral and antiinfectious immune defenses, and to limit viral spread.
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PMID:Cytokines and chemokines in HIV infection: implications for therapy. 964 83

It is now well established that an array of CC and CXC chemokine receptors, in association with the CD4 molecule, can interact with the HIV-1 gp120 protein to facilitate viral fusion. A 32bp deletion in the CC chemokine receptor CCR5, the major M-tropic viral co-receptor, provides considerable protection against HIV-1 transmission and has been associated with a delay in disease progression. The effects of the Delta32 allele appear to be mediated through the phenotype of CCR5 expression as opposed to genotype. Here we discuss the potential effects that the Delta32 allele and other polymorphisms in the chemokine receptor repertoire may have on both HIV-1 transmission and disease progression.
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PMID:Chemokine receptor allelic polymorphisms: relationships to HIV resistance and disease progression. 965 45


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