Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Since the late 1970s, 8.4 million people worldwide, including 1.7 million children, have died of AIDS, and an estimated 22 million people are infected with human immunodeficiency virus (HIV)(1). During 1995 and 1996, major clinical and laboratory discoveries regarding HIV pathogenesis provided new hope for the prevention and treatment of HIV infection. One major discovery was that members of the chemokine receptor family serve as cofactors for HIV entry into cells. We describe the role of allelic polymorphism in the gene coding for the CCR5 chemokine receptor with regard to susceptibility to and disease course of HIV infection. We also examine the effect of this discovery on medical and public health practices.
 ...
PMID:Host genes and HIV: the role of the chemokine receptor gene CCR5 and its allele. 928 70

Persons who are homozygous for the delta32 polymorphism of the CCR5 chemokine receptor gene are highly protected against human immunodeficiency virus type 1 (HIV-1) infection. Previous studies described 54 HIV-1-discordant couples in whom no virus transmission occurred despite extensive sexual contact. The possible role of the delta32 polymorphism in the lack of HIV-1 transmission between these partners was studied. No participants were homozygous for the delta32 allele, but the proportion that was heterozygous was higher among HIV-1-seronegative than HIV-1-seropositive partners (28% vs. 11%, P = .05). This association was seen in heterosexual couples (P = .03) but not in homosexual couples (P = .74). Among white persons, who are most likely to carry the delta32 allele, 38.9% of HIV-1-uninfected and 5.6% of HIV-1-infected heterosexual partners were heterozygous (P = .04). These data are consistent with a possible association between the heterozygous delta32 genotype in heterosexual sex partners and partial protection against HIV-1 infection, and they emphasize the importance of analyzing different risk groups in studies of host factors that influence infection.
 ...
PMID:CCR5 genotypes in sexually active couples discordant for human immunodeficiency virus type 1 infection status. 933 75

The entry of primate immunodeficiency viruses into target cells depends on a sequential interaction of the gp120 envelope glycoprotein with the cellular receptors, CD4 and members of the chemokine receptor family. The gp120 third variable (V3) loop has been implicated in chemokine receptor binding, but the use of the CCR5 chemokine receptor by diverse primate immunodeficiency viruses suggests the involvement of an additional, conserved gp120 element. Through the use of gp120 mutants, a highly conserved gp120 structure was shown to be critical for CCR5 binding. This structure is located adjacent to the V3 loop and contains neutralization epitopes induced by CD4 binding. This conserved element may be a useful target for pharmacologic or prophylactic intervention in human immunodeficiency virus (HIV) infections.
 ...
PMID:A conserved HIV gp120 glycoprotein structure involved in chemokine receptor binding. 966 32

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 natural ligands for the CCR5 chemokine receptor, macrophage inflammatory protein 1alpha (MIP-1alpha), MIP-1beta, and RANTES (regulated on T-cell activation, normal T-cell expressed and secreted), are known to inhibit human immunodeficiency virus (HIV) entry, and N-terminally modified RANTES analogues are more potent than native RANTES in blocking infection. However, potent CCR5 blocking agents may select for HIV-1 variants that use alternative coreceptors at less than fully inhibitory concentrations. In this study, two N-terminal chemical modifications of RANTES produced by total synthesis, aminooxypentane (AOP)-RANTES[2-68] and N-nonanoyl (NNY)-RANTES[2-68], were tested for their ability to prevent HIV-1 infection and to select for coreceptor switch variants in the human peripheral blood lymphocyte-SCID mouse model. Mice were infected with a CCR5-using HIV-1 isolate that requires only one or two amino acid substitutions to use CXCR4 as a coreceptor. Even though it achieved lower circulating concentrations than AOP-RANTES (75 to 96 pM as opposed to 460 pM under our experimental conditions), NNY-RANTES was more effective in preventing HIV-1 infection. However, in a subset of treated mice, these levels of NNY-RANTES rapidly selected viruses with mutations in the V3 loop of envelope that altered coreceptor usage. These results reinforce the case for using agents that block all significant HIV-1 coreceptors for effective therapy.
 ...
PMID:Highly potent RANTES analogues either prevent CCR5-using human immunodeficiency virus type 1 infection in vivo or rapidly select for CXCR4-using variants. 1019 43

A 32-basepair deletion polymorphism in the CCR5 chemokine receptor gene (DeltaCCR5) has recently been identified and shown to have functional significance in determining susceptibility to infection by human immunodeficiency virus type 1 (HIV-1) and a possible influence on disease progression in HIV-1-positive individuals. Interest has also focused on the geographical distribution of the DeltaCCR5 allele, particularly in considering epidemiological aspects of HIV disease and its impact on health economics. In this report we have assessed the frequency of the DeltaCCR5 allele in a Hispanic Mexican population and found a gene frequency of 4.4% in 103 individuals. The DeltaCCR5 allele is not present in indigenous Mexican populations but is present in about 8% of the population in Spain. Gene flow from the European gene pool consistent with Mexico's colonial past would account for the findings in this study.
 ...
PMID:Frequency of the CCR5 gene 32-basepair deletion in Hispanic Mexicans. 1023 69

Simian immunodeficiency virus (SIV) uses the CCR5 chemokine receptor as the main co-receptor to enter CD4+ cells. RANTES, MIP-1alpha and MIP-1beta have been suggested as the major human immunodeficiency virus-suppressor factors produced by CD8+ T-cells. The aim of this study was to investigate the CD8+ T-cell production of anti-viral factors and of beta-chemokines in six cynomolgus macaques vaccinated with live attenuated SIVmacC8 in relation to protection against infectious intrarectal SIVsm challenge. Three of the vaccinated animals were completely protected and one was partially protected against the challenge virus. Interestingly, these monkeys showed higher in vitro anti-viral CD8+ cell suppressor activity and beta-chemokine production both before and after vaccination as compared to the infected monkeys. The results indicate that beta-chemokines may play a role in protective immunity but also that genetic and/or environmental factors may influence their production.
 ...
PMID:Beta-chemokine production in macaques vaccinated with live attenuated virus correlates with protection against simian immunodeficiency virus (SIVsm) challenge. 1042 23

The gp120 envelope glycoprotein of the human immunodeficiency virus type 1 (HIV-1) promotes virus entry by sequentially binding CD4 and chemokine receptors on the target cell. Primary, clinical HIV-1 isolates require interaction with CD4 to allow gp120 to bind the CCR5 chemokine receptor efficiently. We adapted a primary HIV-1 isolate, ADA, to replicate in CD4-negative canine cells expressing human CCR5. The gp120 changes responsible for the adaptation were limited to alteration of glycosylation addition sites in the V2 loop-V1-V2 stem. The gp120 glycoproteins of the adapted viruses bound CCR5 directly, without prior interaction with CD4. Thus, a major function of CD4 binding in the entry of primary HIV-1 isolates can be bypassed by changes in the gp120 V1-V2 elements, which allow the envelope glycoproteins to assume a conformation competent for CCR5 binding.
 ...
PMID:Adaptation of a CCR5-using, primary human immunodeficiency virus type 1 isolate for CD4-independent replication. 1048 61

The human CCR5 chemokine receptor functions as a coreceptor with CD4 for infection by macrophage-tropic isolates of human immunodeficiency virus type 1 (HIV-1). A mutated CCR5 allele which encodes a protein that does not function as a coreceptor for HIV-1 has been identified. Thus, expression of the wild-type and/or mutation allele is relevant to determining the infectability of patient peripheral blood mononuclear cells (PBMC) and affects disease progression in vivo. We developed a qualitative CCR5 genotyping assay using NASBA, an isothermal nucleic acid amplification technology. The method involves three enzymes and two oligonucleotides and targets the CCR5 mRNA, which is expressed in PBMC at a copy number higher than 2, the number of copies of DNA present encoding the gene. The single oligonucleotide set amplifies both alleles, and genotyping is achieved by separate hybridizations of wild-type- and mutation-specific probes directly to the single-stranded RNA amplification product. Assay sensitivity and specificity were demonstrated with RNAs produced in vitro from plasmid clones bearing the DNA encoding each allele. No detectable cross-reactivity between wild-type and mutation probes was found, and 50 copies of each allele were readily detectable. Analysis of patient samples found that 20% were heterozygous and 1% were homozygous for the CCR5 mutation. Thus, NASBA is a sensitive and specific means of rapidly determining CCR5 genotype and provides several technical advantages over alternative assay systems.
 ...
PMID:Genotyping of the CCR5 chemokine receptor by isothermal NASBA amplification and differential probe hybridization. 1054 93

Changes in the envelope glycoprotein ectodomains of a nonpathogenic simian-human immunodeficiency virus (SHIV-89.6) that was serially passaged in vivo have been shown to be responsible for the increased pathogenicity of the resulting virus, SHIV-KB9 (G. B. Karlsson, et al., J. Exp. Med. 188:1159-1171, 1998). The 12 amino acid changes in the envelope glycoprotein ectodomains resulted in increased chemokine receptor-binding and syncytium-forming abilities. Here we identify the envelope glycoprotein determinants of these properties. A single amino acid change in the gp120 third variable (V3) loop was both necessary and sufficient for the observed increase in the binding of the SHIV-KB9 gp120 glycoprotein to the CCR5 chemokine receptor. The increased syncytium-forming ability of SHIV-KB9 involved, in addition to the V3 loop change, changes in the second conserved (C2) region of gp120 (residue 225) and in the gp41 ectodomain (residues 564 and 567). The C2 and gp41 ectodomain changes influenced syncytium formation in a cooperative manner. Changes in the V1/V2 gp120 variable loops exerted a negative effect on syncytium formation and chemokine receptor binding, supporting a previously described role of these changes in immune evasion. The definition of the passage-associated changes that determine the efficiency of chemokine receptor binding and membrane fusogenicity will allow evaluation of the contribution of these properties to in vivo CD4-positive lymphocyte depletion.
 ...
PMID:Envelope glycoprotein determinants of increased fusogenicity in a pathogenic simian-human immunodeficiency virus (SHIV-KB9) passaged in vivo. 1075 60


1 2 3 Next >>