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

Seven transmembrane segment (7TMS) receptors for chemokines and related molecules have been demonstrated to be essential, in addition to CD4, for HIV and SIV infection. The beta-chemokine receptor CCR5 is the primary, perhaps sole, coreceptor for HIV-1 during the early and chronic phases of infection, and supports infection by most primary HIV-1 and many SIV isolates. Late-stage primary and laboratory-adapted HIV-1, HIV-2, and SIV isolates can use other 7TMS receptors. CXCR4 appears especially important in late-stage HIV infection; several related receptors can also be used. The specificity of SIV viruses is similar. Commonalities among these receptors, combined with analyses of mutated molecules, indicate that discrete, conformationally-dependent sites on the chemokine receptors determine their association with the third variable and conserved regions of viral envelope glycoproteins. These studies are useful for elucidating the mechanism and molecular determinants of HIV-1 entry, and of inhibitors to that entry.
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PMID:Chemokine receptors in HIV-1 and SIV infection. 986 29

The discovery of inhibition of HIV-1 by selected chemokines and their receptors instills hope in AIDS researchers, especially because a 32-bp deletion in the chemokine receptor CCR5 (delta32-CCR5) provides resistance to HIV infection. A recent report found that the highest delta32-CCR5 frequency is among Ashkenazi Jews (20.93%). In the present study, we have determined by PCR the allelic frequency of delta32-CCR5 in 520 individuals representing a spectrum of ethnic groups living in Israel. The samples were obtained from the Israeli National Laboratory of Genetic Diversity. Our results showed that Ashkenazi Jews, as to be expected, have the highest frequency (10.19%), yet not significantly higher than that which has been reported for whites of European decent. Other ethnic groups, North African Jews, non-Jews, Middle Eastern Jews, and Ethiopian Jews, gave allelic frequencies of 2.08, 1.35, 1.15, and 0, respectively. Thus, the delta32-CCR5 mutation is found in Jews with the same allelic frequency as that found for residents of their countries of origin. Therefore, it appears that the delta32-CCR5 allele has been introduced into Jewish communities world wide through intermarriage and genetic drift.
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PMID:Distribution of the CCR5 gene 32-base pair deletion in Israeli ethnic groups. 992 34

Binding of the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein gp120 to both CD4 and one of several chemokine receptors (coreceptors) permits entry of virus into target cells. Infection of tissues may establish latent viral reservoirs as well as cause direct pathologic effects that manifest as clinical disease such as HIV-associated dementia. We sought to identify the critical coreceptors recognized by HIV-1 tissue-derived strains as well as to correlate these coreceptor preferences with site of infection and dementia diagnosis. To reconstitute coreceptor use, we cloned HIV-1 envelope V3 sequences encoding the primary determinants of coreceptor specificity from 13 brain-derived and 6 colon-derived viruses into an isogenic (NL4-3) viral background. All V3 recombinants utilized the chemokine receptor CCR5 uniformly and efficiently as a coreceptor but not CXCR4, BOB/GPR15, or Bonzo/STRL33. Other receptors such as CCR3, CCR8, and US28 were inefficiently and variably used as coreceptors by various envelopes. CCR5 without CD4 present did not allow for detectable infection by any of the tested recombinants. In contrast to the pathogenic switch in coreceptor specificity frequently observed in comparisons of blood-derived viruses early after HIV-1 seroconversion and after onset of AIDS, the characteristics of these V3 recombinants suggest that CCR5 is a primary coreceptor for brain- and colon-derived viruses regardless of tissue source or diagnosis of dementia. Therefore, tissue infection may not depend significantly on viral envelope quasispeciation to broaden coreceptor range but rather selects for CCR5 use throughout disease progression.
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PMID:V3 recombinants indicate a central role for CCR5 as a coreceptor in tissue infection by human immunodeficiency virus type 1. 997 18

The vertebrate immune system has evolved to respond vigorously to microbial infection but to ignore self-antigens. Evidence has emerged that B cell responses to viruses are initiated by immune recognition of ordered arrays of antigen on the viral surface. To test whether autoantibodies against a self-antigen can be induced by placing it in a context that mimics the ordered surface of a viral particle, a peptide representing an extracellular loop of the mouse chemokine receptor CCR5 was incorporated into an immunodominant site of the bovine papillomavirus virus L1 coat protein, which self-assembles into virus-like particles. Mice inoculated with chimeric L1-CCR5 particles generated autoantibodies that bound to native mouse CCR5, inhibited binding of its ligand RANTES, and blocked HIV-1 infection of an indicator cell line expressing a human-mouse CCR5 chimera. These results suggest a general method for inducing autoantibodies against self-antigens, with diverse potential basic research and clinical applications.
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PMID:Induction of autoantibodies to mouse CCR5 with recombinant papillomavirus particles. 1005 49

Chemokine receptors and related seven-transmembrane-segment (7TMS) receptors serve as coreceptors for entry of human and simian immunodeficiency viruses (HIV-1, HIV-2, and SIV) into target cells. Each of these otherwise diverse coreceptors contains an N-terminal region that is acidic and tyrosine rich. Here, we show that the chemokine receptor CCR5, a principal HIV-1 coreceptor, is posttranslationally modified by O-linked glycosylation and by sulfation of its N-terminal tyrosines. Sulfated tyrosines contribute to the binding of CCR5 to MIP-1 alpha, MIP-1 beta, and HIV-1 gp120/CD4 complexes and to the ability of HIV-1 to enter cells expressing CCR5 and CD4. CXCR4, another important HIV-1 coreceptor, is also sulfated. Tyrosine sulfation may contribute to the natural function of many 7TMS receptors and may be a modification common to primate immunodeficiency virus coreceptors.
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PMID:Tyrosine sulfation of the amino terminus of CCR5 facilitates HIV-1 entry. 1008 82

The most common form of mutation found in the CCR5 gene has been the precise 32-base pair (bp) deletion in the region corresponding to second extracellular loop of the chemokine receptor CCR5. Individuals homozygous for the delta 32 allele of CCR5 usually remain uninfected despite multiple exposures to HIV, whereas heterozygous individuals support less virus replication and show slower progression of the disease. This mutant allele in either homozygous or heterozygous form is quite common in white people of European heritage. Earlier work involving large populations of Asians and Africans failed to detect the presence of this mutant allele. We screened 145 normal unrelated healthy Indians and found one person who was heterozygous for the delta 32 allele of CCR5. We studied the inheritance of this deleted allele in this person's family. One parent, one of two sons, and the only daughter possessed this mutant allele. We cloned the entire coding region of wild-type and mutant alleles of CCR5 gene from the heterozygous individual mentioned and studied its coreceptor functions. The mutant allele had only a moderate interfering effect on coreceptor activity of the wild-type CCR5 allele in a cell fusion assay. We also report an improved method of genotyping CCR5 gene in this communication.
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PMID:Inheritance pattern of mutant human immunodeficiency virus type 1 coreceptor gene CCR5 in an Indian family. 1019 41

RANTES (regulated on activation normal T cell expressed and secreted) is one of the natural ligands for the chemokine receptor CCR5 and potently suppresses in vitro replication of the R5 strains of HIV-1, which use CCR5 as a coreceptor. Previous studies showed that peripheral blood mononuclear cells or CD4(+) lymphocytes obtained from different individuals had wide variations in their ability to secrete RANTES. These findings prompted us to analyze the upstream noncoding region of the RANTES gene, which contains cis-acting elements involved in RANTES promoter activity, in 272 HIV-1-infected and 193 non-HIV-1-infected individuals in Japan. Our results showed that there were two polymorphic positions, one of which was associated with reduced CD4(+) lymphocyte depletion rates during untreated periods in HIV-1-infected individuals. This mutation, RANTES-28G, occurred at an allele frequency of approximately 17% in the non-HIV-1-infected Japanese population and exerted no influence on the incidence of HIV-1 infection. Functional analyses of RANTES promoter activity indicated that the RANTES-28G mutation increases transcription of the RANTES gene. Taken together, these data suggest that the RANTES-28G mutation increases RANTES expression in HIV-1-infected individuals and thus delays the progression of the HIV-1 disease.
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PMID:Polymorphism in RANTES chemokine promoter affects HIV-1 disease progression. 1020 Mar 5

The beta-chemokine receptor CCR5 is considered to be an attractive target for inhibition of macrophage-tropic (CCR5-using or R5) HIV-1 replication because individuals having a nonfunctional receptor (a homozygous 32-bp deletion in the CCR5 coding region) are apparently normal but resistant to infection with R5 HIV-1. In this study, we found that TAK-779, a nonpeptide compound with a small molecular weight (Mr 531.13), antagonized the binding of RANTES (regulated on activation, normal T cell expressed and secreted) to CCR5-expressing Chinese hamster ovary cells and blocked CCR5-mediated Ca2+ signaling at nanomolar concentrations. The inhibition of beta-chemokine receptors by TAK-779 appeared to be specific to CCR5 because the compound antagonized CCR2b to a lesser extent but did not affect CCR1, CCR3, or CCR4. Consequently, TAK-779 displayed highly potent and selective inhibition of R5 HIV-1 replication without showing any cytotoxicity to the host cells. The compound inhibited the replication of R5 HIV-1 clinical isolates as well as a laboratory strain at a concentration of 1.6-3.7 nM in peripheral blood mononuclear cells, though it was totally inactive against T-cell line-tropic (CXCR4-using or X4) HIV-1.
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PMID:A small-molecule, nonpeptide CCR5 antagonist with highly potent and selective anti-HIV-1 activity. 1031 47

Primary isolates of human and simian immunodeficiency viruses (HIV and SIV) use the chemokine receptor CCR5, in association with CD4, as coreceptor. During AIDS progression, HIV-1 and HIV-2 often adapt to use additional cofactors, particularly CXCR4. In contrast, SIV isolates do not use CXCR4, but other coreceptors such as BOB/GPR15 and Bonzo/STRL33. Only limited information is currently available on usage of BOB/GPR15 and Bonzo/STRL33 by HIV-1. Therefore, we investigated a panel of gp160 clones from 15 primary isolates, representing 5 different subtypes, for utilization of these cofactors. The majority of HIV-1 envelopes mediated entry into BOB/GPR15-expressing cells, albeit often with low efficiency. Usage of Bonzo/STRL33 was less common and usually inefficient. To investigate if HIV-1 entry via these orphan receptors is sufficient to allow virus replication, 15 uncloned primary HIV-1 isolates and 7 molecular clones were used to infect target cells expressing CD4 and Bonzo/STRL33 or BOB/GPR15. Three primary isolates and two molecular clones replicated efficiently in cells expressing BOB/GPR15. Two of these isolates were X4-tropic, two were R5X4-tropic and one was R5-tropic. In contrast, none of the HIV-1 variants showed significant levels of replication in Bonzo/STRL33-expressing cells. Our data show that some HIV-1 isolates of different genetic subtype and of different biological phenotype use BOB/GPR15 for productive infection and suggest that this cofactor may play a role in HIV-1 pathogenesis and transmission.
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PMID:Coreceptor usage of BOB/GPR15 and Bonzo/STRL33 by primary isolates of human immunodeficiency virus type 1. 1035 71

Macrophage (M)-tropic HIV-1 isolates use the beta-chemokine receptor CCR5 as a coreceptor for entry, while T cell line-adapted (TCLA) strains use CXCR4 and dual-tropic strains can use either CCR5 or CXCR4. To investigate the viral determinants involved in choice of coreceptor, we used a fusion assay based on the infection of CD4+ HeLa cells that express one or both coreceptors with Semliki Forest virus (SFV) recombinants expressing the native HIV-1 gp160 of a primary M-tropic isolate (HIV-1BX08), a TCLA isolate (HIV-1LAI), or a dual-tropic strain (HIV-1MN). We examined whether the V3 region of these glycoproteins interacts directly with the corresponding coreceptors by assaying coreceptor-dependent cell-to-cell fusion mediated by the different recombinants in the presence of various synthetic linear peptides. Synthetic peptides corresponding to different V3 loop sequences blocked syncytium formation in a coreceptor-specific manner. Synthetic V2 peptides were also inhibitory for syncytium formation, but showed no apparent coreceptor specificity. A BX08 V3 peptide with a D320 --> R substitution retained no inhibitory capacity for BX08 Env-mediated cell-to-cell fusion, but inhibited LAI Env-mediated fusion as efficiently as the homologous LAI V3 peptide. The same mutation engineered in the BX08 env gene rendered it able to form syncytia on CD4+CXCR4+CCR5-HeLa cells and susceptible to inhibition by SDF-1alpha and MIP-1beta. Other substitutions tested (D320 --> Q/D324 --> N or S306 --> R) exhibited intermediate effects on coreceptor usage. These results underscore the importance of the V3 loop in modulating coreceptor choice and show that single amino acid modifications in V3 can dramatically modify coreceptor usage. Moreover, they provide evidence that linear V3 loop peptides can compete with intact cell surface-expressed gp120/gp41 for CCR5 or CXCR4 interaction.
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PMID:Role of the HIV type 1 glycoprotein 120 V3 loop in determining coreceptor usage. 1035 69


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