Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0265264 (HOS)
 1,119 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The recent identification of coreceptors that mediate efficient entry of human immunodeficiency virus type 1 (HIV-1) suggests new therapeutic and preventive strategies. We analyzed simian immunodeficiency virus (SIV) entry cofactors to investigate whether the macaque SIV model can be used as an experimental model to evaluate these strategies. Similar to primary HIV-1 isolates, a well-characterized molecular clone, SIVmac239, which replicates poorly but efficiently enters into rhesus alveolar macrophages and an envelope variant, SIVmac239/316Env, with an approximately 1,000-fold-higher replicative capacity in macrophages used the beta-chemokine receptor CCR5 for efficient entry. The transmembrane portion of 316Env allowed low-level entry into cells expressing CCR1, CCR2B, and CCR3. A single amino acid substitution in the V3 loop of SIVmac239/316Env, 321P-->S, impaired the ability to enter into the T-B hybrid cell line CEMx174 but had relatively little effect on entry into primary cells and HOS.CD4 cells expressing CCR5. Although CEMx174 cells do not express CCR5, most SIVmac variants entered this hybrid cell line efficiently but did not enter the parental T-cell line CEM. It seems likely that CEMx174 cells express an as-yet-unidentified, perhaps B-cell-derived cofactor which allows efficient entry of SIVmac.
 ...
PMID:Simian immunodeficiency virus variants with differential T-cell and macrophage tropism use CCR5 and an unidentified cofactor expressed in CEMx174 cells for efficient entry. 926 70

The chemokine receptors CCR5 and CXCR4, in combination with CD4, mediate cellular entry of macrophage-tropic (M-tropic) and T-cell-tropic strains of human immunodeficiency virus type 1 (HIV-1), respectively, while dualtropic viruses can use either receptor. We have constructed a panel of chimeric viruses and envelope glycoproteins in which various domains of the dualtropic HIV-1(DH12) gp160 were introduced into the genetic background of an M-tropic HIV-1 isolate, HIV-1(AD8). These constructs were employed in cell fusion and virus infectivity assays using peripheral blood mononuclear cells, MT4 T cells, primary monocyte-derived macrophages, or HOS-CD4 cell lines, expressing various chemokine receptors, to assess the contributions of different gp120 subdomains in coreceptor usage and cellular tropism. As expected, the dualtropic HIV-1(DH12) gp120 utilized either CCR3, CCR5, or CXCR4, whereas HIV-1(AD8) gp120 was able to use only CCR3 or CCR5. We found that either the V1/V2 or the V3 region of HIV-1(DH12) gp120 individually conferred on HIV-1(AD8) the ability to use CXCR4, while the combination of both the V1/V2 and V3 regions increased the efficiency of CXCR4 use. In addition, while the V4 or the V5 region of HIV-1(DH12) gp120 failed to confer the capacity to utilize CXCR4 on HIV-1(AD8), these regions were required in conjunction with regions V1 to V3 of HIV-1(DH12) gp120 for efficient utilization of CXCR4. Comparison of virus infectivity analyses with various cell types and cell fusion assays revealed assay-dependent discrepancies and indicated that events occurring at the cell surface during infection are complex and cannot always be predicted by any one assay.
 ...
PMID:Identification of determinants on a dualtropic human immunodeficiency virus type 1 envelope glycoprotein that confer usage of CXCR4. 949 15

A new member of human beta-chemokine cDNA was isolated and named leukotactin-1 (Lkn-1). Lkn-1, along with murine macrophage inflammatory protein-related protein-1 and -2, defines a subgroup of beta-chemokines based on two conserved cysteines in addition to the four others conserved in all beta-chemokines. The putative mature Lkn-1 is composed of 92 amino acids with a calculated m.w. of 10,162. The Lkn-1 gene was mapped to human chromosome 17, region q12. Recombinant Lkn-1 was a potent chemoattractant for neutrophils, monocytes, and lymphocytes and induced calcium flux in these cells. Lkn-1 specifically induced calcium flux in CCR1- and CCR3-expressing HOS cell lines. Lkn-1 suppressed colony formation by human granulocyte-macrophage, erythroid, and multipotential progenitor cells stimulated by combinations of growth factors. Hence, we have isolated and characterized a human C6 beta-chemokine that is a potent agonist at CCR1 and CCR3 and shows broad biologic activities, including leukocyte chemoattraction.
 ...
PMID:Molecular cloning of leukotactin-1: a novel human beta-chemokine, a chemoattractant for neutrophils, monocytes, and lymphocytes, and a potent agonist at CC chemokine receptors 1 and 3. 954 57

The NL4.3 T-cell-line-tropic human immunodeficiency virus type 1 strain is sensitive to the CXC chemokine stromal cell-derived factor 1alpha (SDF-1alpha), the natural ligand for CXC chemokine receptor 4 (CXCR4); the 50% inhibitory concentration (IC50) in MT-4 cells is 130 ng/ml. We generated resistant virus through passaging of the virus in the presence of increasing concentrations of SDF-1alpha. After 24 passages, the virus was no longer sensitive to SDF-1alpha (SDF-1alpha(res) virus) (IC50, >2 microg/ml) and became resistant to SDF-1beta (IC50, >2 microg/ml) and to a specific CXCR4 monoclonal antibody (IC50, >20 microg/ml). The SDF-1alpha(res) virus was about 10-fold less sensitive than the wild-type virus to the bicyclam AMD3100, a specific CXCR4 antagonist. The SDF-1alpha(res) virus contained the following mutations in the gp120 molecule: N106K in the V1 loop; S134N and F145L in the V2 loop; F245I in the C2 loop; K269E, Q278H, I288V, and N293D in the V3 loop; a deletion of 5 amino acids (FNSTW) at positions 364 to 368 in the V4 loop; and R378T in the CD4 binding domain. Replication of the NL4.3 wild-type virus and the SDF-1alpha(res) virus was demonstrated in U87 cells that coexpressed CD4 and CXCR4 (U87.CD4.CXCR4) but not in U87.CD4.CCR5 cells. Thus, the resistant virus was not able to switch to the CC chemokine receptor 5 (CCR5) coreceptor (the main coreceptor for macrophage-tropic viruses). The SDF-1alpha(res) virus replicated in HOS.CD4 cells expressing CCR1, CCR2b, CCR3, CCR4, CCR5, and CXCR4 but also in HOS.CD4.pBABE cells. However, all HOS transfectant cells expressed a low level of CXCR4. Neither of the two virus strains was able to infect HOS.CXCR4 or HOS.CCR5 transfectants, demonstrating the necessity of the CD4 receptor. The T-cell-line-tropic SDF-1alpha(res) virus was thus able to overcome the inhibitory effect of SDF-1alpha through mutations in gp120 but still needed CXCR4 to enter the cells.
 ...
PMID:T-cell-line-tropic human immunodeficiency virus type 1 that is made resistant to stromal cell-derived factor 1alpha contains mutations in the envelope gp120 but does not show a switch in coreceptor use. 955 91

The simian immunodeficiency virus (SIV) mnd(GB-1) strain, isolated from a mandrill, replicates in a human T cell line, CEM cells, and is inhibited by the CXC-chemokines, stromal cell-derived factor 1alpha and 1beta (SDF-1alpha/SDF-1beta), the natural ligands for CXCR4. The IC50 was around 70-80 ng/ml, which corresponds to the IC50 of SDF-1alpha/SDF-1beta for T-tropic human immunodeficiency virus type 1 (HIV-1) and HIV-2. The specific anti-CXCR4 MAb 12G5 inhibited replication of SIVmnd at an IC50 of 1 microg/ml. Also, the IC50 of 8 ng/ml for SIVmnd of the bicyclam AMD3100, a specific CXCR4 antagonist, is comparable with its IC50 for T-tropic HIV-1 and HIV-2 strains. Two other SIV strains, SIVagm3 and SIVmac251, were insensitive to SDF-1alpha/SDF-1beta, anti-CXCR4 MAb and AMD3100. SIVmnd replicates only in HOS.CD4 cells expressing CXCR4 and not in HOS.CD4 transfectants expressing CCR1, CCR2b, CCR3, CCR4 or CCR5. This is, to our knowledge, the first SIV strain found to use CXCR4 and not CCR5 as a main coreceptor for entering human cells.
 ...
PMID:The simian immunodeficiency virus mnd(GB-1) strain uses CXCR4, not CCR5, as coreceptor for entry in human cells. 974 29

We tested chemokine receptor subset usage by diverse, well-characterized primary viruses isolated from peripheral blood by monitoring viral replication with CCR1, CCR2b, CCR3, CCR5, and CXCR4 U87MG.CD4 transformed cell lines and STRL33/BONZO/TYMSTR and GPR15/BOB HOS.CD4 transformed cell lines. Primary viruses were isolated from 79 men with confirmed human immunodeficiency virus type 1 (HIV-1) infection from the Chicago component of the Multicenter AIDS Cohort Study at interval time points. Thirty-five additional well-characterized primary viruses representing HIV-1 group M subtypes A, B, C, D, and E and group O and three primary simian immunodeficiency virus (SIV) isolates were also used for these studies. The restricted use of the CCR5 chemokine receptor for viral entry was associated with infection by a virus having a non-syncytium-inducing phenotype and correlated with a reduced rate of disease progression and a prolonged disease-free interval. Conversely, broadening chemokine receptor usage from CCR5 to both CCR5 and CXCR4 was associated with infection by a virus having a syncytium-inducing phenotype and correlated with a faster rate of CD4 T-cell decline and progression of disease. We also observed a greater tendency for infection with a virus having a syncytium-inducing phenotype in men heterozygous for the defective CCR5 Delta32 allele (25%) than in those men homozygous for the wild-type CCR5 allele (6%) (P = 0.03). The propensity for infection with a virus having a syncytium-inducing phenotype provides a partial explanation for the rapid disease progression among some men heterozygous for the defective CCR5 Delta32 allele. Furthermore, we did not identify any primary viruses that used CCR3 as an entry cofactor, despite this CC chemokine receptor being expressed on the cell surface at a level commensurate with or higher than that observed for primary peripheral blood mononuclear cells. Whereas isolates of primary viruses of SIV also used STRL33/BONZO/TYMSTR and GPR15/BOB, no primary isolates of HIV-1 used these particular chemokine receptor-like orphan molecules as entry cofactors, suggesting a limited contribution of these other chemokine receptors to viral evolution. Thus, despite the number of chemokine receptors implicated in viral entry, CCR5 and CXCR4 are likely to be the physiologically relevant chemokine receptors used as entry cofactors in vivo by diverse strains of primary viruses isolated from blood.
 ...
PMID:Chemokine coreceptor usage by diverse primary isolates of human immunodeficiency virus type 1. 976 80

The utility of the GHOST(3) cell assay has been evaluated for testing coreceptor use of primary human immunodeficiency virus type 1 (HIV-1) isolates. GHOST(3) cells were derived from the human osteosarcoma cell line, HOS, and have been engineered to stably express CD4 and one or another of the chemokine receptors CCR3, CCR5, CXCR4, Bonzo, or the orphan receptor BOB. The indicator cell line carries the HIV-2 long terminal repeat-driven green fluorescence protein (GFP) gene, which becomes activated upon infection with HIV or simian immunodeficiency virus. Viral entry is followed by Tat activation of transcription and GFP becomes expressed. Infected cells can be detected 2 or 3 days after infection by simple fluorescence microscopic observation. This simplicity is the main advantage of the GHOST(3) cell system and makes it particularly suitable for screening of a large number of isolates. In addition, the efficiency of coreceptor use can be accurately quantitated with flow cytometric analysis. Here, we evaluated the coreceptor use of 59 primary HIV-1 isolates of different subtypes.
 ...
PMID:Quantitative evaluation of HIV-1 coreceptor use in the GHOST3 cell assay. 1187 71

An assay has been established for quantitative evaluation of lentivirus coreceptor use with the help of GHOST(3) cells. GHOST(3) cells were derived from the human osteosarcoma cell line, HOS, and have been engineered to stably express CD4 and one or another of the chemokine receptors CCR3, CCR5, CXCR4, CXCR6/STRL33/Bonzo, or the orphan receptor GPR15/BOB. The indicator cell line carries the HIV-2 long terminal repeat-driven green fluorescence protein (GFP) gene, which becomes activated upon infection with HIV or SIV. Viral entry is followed by Tat activation of transcription and GFP becomes expressed. Infected cells can be detected as early as 2 or 3 d after infection by simple fluorescence microscopic observation. The simplicity of the GHOST(3) cell system makes it particularly suitable for screening of a large number of isolates. In addition, the efficiency of co-receptor use can be accurately quantitated with flow cytometric analysis. Thus, the most efficiently used co-receptor of multitropic isolates can be determined. It is also possible to sensitively determine co-receptor switch of sequential isolates from the same individual.
 ...
PMID:Quantitative evaluation of HIV and SIV co-receptor use with GHOST(3) cell assay. 1606 87