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

Resistance to HIV-1 infection and delayed disease progression have been associated with a 32-bp deletion (Delta32) in the gene encoding the CCR5 chemokine receptor. In the present study we describe the modification of a nucleic acid sequence-based amplification (NASBA)-based CCR5 genotyping assay for a NucliSens Basic Kit (Organon Teknika, Durham, N.C.) format using a new target-specific sandwich oligonucleotide detection methodology. The new method permitted the use of generic electrochemiluminescent probes supplied in the NucliSens Basic Kit, whereas the original NASBA method required expensive target-specific ruthenium detection probes. The Basic Kit CCR5 Delta32 genotypic analysis was in 100% concordance with both the original NASBA assay and DNA PCR results. This study also evaluated the use of multiple specimen types, including peripheral blood mononuclear cells (PBMC), whole blood, dried blood spots, buccal scrapings, and plasma, for CCR5 genotype analysis. The sensitivities of the three assays were comparable when PBMC or whole blood was the specimen source. In contrast, when dried blood spots, buccal scrapings, or plasma was used as the sample source, the sensitivity of DNA PCR was 80.95, 42.8, or 0%, respectively, compared to 100% sensitivity obtained with the original NASBA and Basic Kit NASBA assays. Our study indicates that the NucliSens Basic Kit NASBA assay is very sensitive and specific for CCR5 Delta32 genotyping using multiple sample types.
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PMID:Chemokine receptor CCR5 Delta 32 genetic analysis using multiple specimen types and the NucliSens Basic Kit. 1152 12

The molecular mechanism of human immunodeficiency virus type 1 (HIV-1) entry into cells involves specific interactions between the viral envelope glycoprotein gp120 and two target cell proteins, CD4 and either CCR5 or CXCR4 chemokine receptors. In order to delineate the functional role of HIV-1 gp120 subdomains of dualtropic strains in CCR5 coreceptor usage, we used a panel of chimeric viruses in which the V1/V2 and V3 domains of gp120 from the dualtropic HIV-1(KMT) isolate were introduced either alone or in combination into the T-tropic HIV-1(NL4-3) background. These chimeric constructs were employed in cell-cell fusion and cell-free virus infectivity assays using cell lines expressing CD4 and the CCR5 chemokine receptor. In both assays, the V3 domain of HIV-1(KMT) but not the V1/V2 domain proved to be the principal determinant of CCR5 coreceptor usage. However, in the cell-free viral infectivity assay although a chimeric virus with a combined V1/V2 and V3 domains of HIV-1(KMT) efficiently fused with coreceptor expressing cells, yet its infectivity was markedly diminished in CCR5 as well as CXCR4 expressing cells. Restoring a comparable level of infection of such chimeric virus required the C3-V5 domain from HIV-1(KMT) to be introduced. Our present findings confirmed that the V3 domain is the major determinant of fusion activity and cellular tropism, and demonstrated a dispensable role for the V1/V2 domain. In addition the C3-V5 domain appeared to play an important role in viral infectivity when the corresponding V1/V2 and V3 domains are present.
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PMID:Role of V3 independent domains on a dualtropic human immunodeficiency virus type 1 (HIV-1) envelope gp120 in CCR5 coreceptor utilization and viral infectivity. 1152 58

The human immunodeficiency virus, type 1 (HIV-1) entry process is triggered by interaction between the viral envelope and a seven membrane-spanning domain receptor at the cell surface, usually the CCR5 chemokine receptor. Different naturally occurring mutations in the CCR5 gene abolish receptor function, the most frequent being a 32-nucleotide deletion resulting in a truncated protein (Delta32) lacking the last three transmembrane domains (TM5-7). This mutant is retained in the endoplasmic reticulum and exerts a trans-dominant negative (TDN) effect on the wild type, preventing its exit from this compartment. This TDN effect is often considered as evidence for the oligomerization of CCR5 during transport to the cell surface. Here we use a genetic approach to define the structural determinants of the TDN effect of the Delta32 mutant. It was abolished by certain deletions and by mutations of cysteine residues preventing formation of a disulfide link between the first and second extracellular loops, suggesting that conformation of Delta32 is important for its interaction with CCR5. To circumvent this problem, we used chimeric forms of the Delta32 and wild type CCR5, consisting in substitutions with homologous domains from the mouse CCR5. All chimeric full-length receptors were expressed at the cell surface and were functional for interaction with HIV-1 or with a chemokine ligand, when assayed. The TDN effect was only observed if both the TM3 domain in CCR5 and the TM4 domain in Delta32 were from human origin, whereas the rest of the proteins could be from either origin. This suggests that the TDN effect involves some form of interaction between these transmembrane domains. Alternatively, but less likely to us, substitutions in TM4 could affect the conformation of CCR5 in the endoplasmic reticulum but not at the cell surface. However that may be, it seems that the TDN effect of the Delta32 mutant has no bearing to the issue of CCR5 dimerization and to its possible role in the processing of the receptor to the cell surface.
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PMID:Determinants of the trans-dominant negative effect of truncated forms of the CCR5 chemokine receptor. 1160 Apr 94

The effect of polymorphisms on genes encoding the CCR5 chemokine receptor and vitamin D receptor (VDR) in human immunodeficiency virus (HIV) type 1 disease progression was analyzed in a cohort of 185 HIV-seropositive injection drug users. Results confirmed a lack of association in patients with HIV disease between CCR5 wtDelta32 heterozygosity and a slow progression to AIDS and to a CD4 cell count <200 cells/microL. In contrast, a more rapid disease progression was associated with the VDR-BB genotype. A higher proportion of this genotype was found in patients with <200 CD4 cells/microL (P=.009; odds ratio [OR], 2.4; 95% confidence interval [CI], 1.3-4.7), as well as a faster progression both to AIDS (1993 CDC classification [CDC 1993]) and to a CD4 cell count <200 cells/microL. When the analysis was restricted to patients with a VDR-bb genetic background, patients with CCR5 wtDelta32 heterozygosity were overrepresented in CDC 1993 nonprogressors (P=.033; OR, 0.28; 95% CI, 0.08-0.92) and in those with >200 CD4 cells/microL (P=.062; OR, 0.26; 95% CI, 0.06-1.08). Also, patients with CCR5 wtDelta32 heterozygosity showed a slow progression both to AIDS CDC 1993 and to a CD4 cell count <200 cells/microL.
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PMID:Host genetic background at CCR5 chemokine receptor and vitamin D receptor loci and human immunodeficiency virus (HIV) type 1 disease progression among HIV-seropositive injection drug users. 1167 16

It's well-known that the homozygous type of two copies of the 32 base pair deletion in the CCR5 chemokine receptor provides resistance to HIV-1 infection. But there have been fewer data pertaining to what happens when a person has only one copy of the CCR5 delta 32 genotype. A recent study shows that even heterozygous CCR5 32 genotype, found primarily in European Caucasians, provides significant protection from infection during exposure to HIV-1.
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PMID:One copy of mutation may help resistance: study. 1186 45

Interaction of the human immunodeficiency virus (HIV-1) envelope glycoproteins with the CCR5 chemokine receptor, a G-protein-coupled receptor, triggers a membrane fusion process and virus entry. Cooperation for HIV-1 receptor activity was observed when two forms of CCR5 were coexpressed, either the wild-type (WT) receptor and a defective mutant with deletion of the amino-terminal (NT) extracellular domain or the latter deltaNT mutant and a human-mouse CCR5 chimera bearing the NT domain from human CCR5. Cooperation was most efficient when the two forms of CCR5 were in a 1:1 ratio. It was not observed between the CCR5 deltaNT mutant and a chimeric receptor (5444) in which the NT domain of CCR5 was in the context of another G-protein-coupled receptor, the HIV-1 receptor CXCR4. These results suggested that physical association between two forms of CCR5 was required for their cooperation. Coimmunoprecipitation experiments in transfected cell lysates indeed showed that the deltaNT CCR5 mutant formed oligomeric complexes with the WT CCR5 or the HMMM chimera but not with the CXCR4-derived chimera 5444. These observations suggest that the formation of CCR5 oligomers is a constitutive process independent from activation by chemokine ligands. The interaction of HIV-1 with independent subunits of CCR5 oligomers could favor the local recruitment of fusiogenic proteins and the formation of a fusion pore.
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PMID:Rescue of HIV-1 receptor function through cooperation between different forms of the CCR5 chemokine receptor. 1215 92

The entry of human immunodeficiency virus (HIV-1) into target cells typically requires the sequential binding of the viral exterior envelope glycoprotein, gp120, to CD4 and a chemokine receptor. CD4 binding exposes gp120 epitopes recognized by CD4-induced (CD4i) antibodies, which can block virus binding to the chemokine receptor. We identified three new CD4i antibodies from an HIV-1-infected individual and localized their epitopes. These epitopes include a highly conserved gp120 beta-strand encompassing residues 419-424, which is also important for binding to the CCR5 chemokine receptor. All of the CD4i antibodies inhibited the binding of gp120-CD4 complexes to CCR5. CD4i antibodies and CD4 reciprocally induced each other's binding, suggesting that these ligands recognize a similar gp120 conformation. The CD4i antibodies neutralized laboratory-adapted HIV-1 isolates; primary isolates were more resistant to neutralization by these antibodies. Thus, all known CD4i antibodies recognize a common, conserved gp120 element overlapping the binding site for the CCR5 chemokine receptor.
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PMID:Characterization of CD4-induced epitopes on the HIV type 1 gp120 envelope glycoprotein recognized by neutralizing human monoclonal antibodies. 1248 27

Homozygous sickle cell disease (SCD) has a wide spectrum of clinical manifestations. In Brazil, the main cause of death of individuals with SCD is recurrent infection. The CCR5delta32 allele, which confers relative resistance to macrophage-tropic HIV virus infection, probably has reached its frequency and world distribution due to other pathogens that target macrophage in European populations. In the present investigation a relatively higher prevalence (5.1%) of the CCR5delta32 allele was identified, by PCR amplification using specific primers, in 79 SCD patients when compared to healthy controls (1.3%) with the same ethnic background (Afro-Brazilians). Based on a hypothesis that considers SCD as a chronic inflammatory condition, and since the CCR5 chemokine receptor is involved in directing a Th1-type immune response, we suggest that a Th1/Th2 balance can influence the morbidity of SCD. If the presence of the null CCR5delta32 allele results in a reduction of the chronic inflammation state present in SCD patients, this could lead to differential survival of SCD individuals who are carriers of the CCR5delta32 allele. This differential survival could be due to the development of less severe infections and consequently reduced or less severe vaso-occlusive crises.
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PMID:High frequency of the CCR5delta32 variant among individuals from an admixed Brazilian population with sickle cell anemia. 1253 29

Early in infection, human immunodeficiency virus type 1 (HIV-1) generally uses the CCR5 chemokine receptor (along with CD4) for cellular entry. In many HIV-1-infected individuals, viral genotypic changes arise that allow the virus to use CXCR4 (either in addition to CCR5 or alone) as an entry coreceptor. This switch has been associated with an acceleration of both CD3(+) T-cell decline and progression to AIDS. While it is well known that the V3 loop of gp120 largely determines coreceptor usage and that positively charged residues in V3 play an important role, the process of genetic change in V3 leading to altered coreceptor usage is not well understood. Further, the methods for biological phenotyping of virus for research or clinical purposes are laborious, depend on sample availability, and present biosafety concerns, so reliable methods for sequence-based "virtual phenotyping" are desirable. We introduce a simple bioinformatic method of scoring V3 amino acid sequences that reliably predicts CXCR4 usage (sensitivity, 84%; specificity, 96%). This score (as determined on the basis of position-specific scoring matrices [PSSM]) can be interpreted as revealing a propensity to use CXCR4 as follows: known R5 viruses had low scores, R5X4 viruses had intermediate scores, and X4 viruses had high scores. Application of the PSSM scoring method to reconstructed virus phylogenies of 11 longitudinally sampled individuals revealed that the development of X4 viruses was generally gradual and involved the accumulation of multiple amino acid changes in V3. We found that X4 viruses were lost in two ways: by the dying off of an established X4 lineage or by mutation back to low-scoring V3 loops.
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PMID:Improved coreceptor usage prediction and genotypic monitoring of R5-to-X4 transition by motif analysis of human immunodeficiency virus type 1 env V3 loop sequences. 1464 92

The CCR5 chemokine receptor has recently been found to play a crucial role in the viral entry stage of HIV infection and has therefore become an attractive potential target for anti-HIV therapeutics. On the other hand, the lack of CCR5 crystal structure data has impeded the development of structure-based CCR5 antagonist design. In this paper, we compare two three-dimensional Quantitative Structure-Activity Relationship (3D-QSAR) methods: Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) on a series of piperidine-based CCR5 antagonists as an alternative approach to investigate the interaction between CCR5 antagonists and their receptor. Superimposition of antagonist structures was performed using two alignment rules: atomic/centroid rms fit and rigid body field fit techniques. The 3D QSAR models were derived from a training set of 72 compounds, and were found to have predictive capability for a set of 19 holdout test compounds. The resulting contour maps produced by the best CoMFA and CoMSIA models were used to identify the structural features relevant to biological activity in this series of compounds. Further analyses of these interaction-field contour maps also showed a high level of internal consistency.
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PMID:Three-dimensional quantitative structure-activity relationship analyses of piperidine-based CCR5 receptor antagonists. 1472 67


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