Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0001175 (AIDS)
 120,706 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CCR5 encodes a cell surface chemokine receptor molecule that serves as the principal coreceptor, with CD4, for HIV-type 1 (HIV-1). Varied HIV-1 susceptibility and time to progression to AIDS have been associated with polymorphisms in CCR5. Many of these polymorphisms are located in the 5' cis-regulatory region of CCR5, suggesting that it may have been a target of natural selection. We characterized CCR5 sequence variation in this region in 400 chromosomes from worldwide populations and compared it to a genome-wide analysis of 100 Alu polymorphisms typed in the same populations. Variation was substantially higher than expected and characterized by an excess of intermediate-frequency alleles. A genealogy of CCR5 haplotypes had deep branch lengths despite markedly little differentiation among populations. This finding suggested a deviation from neutrality not accounted for by population structure, which was confirmed by tests for natural selection. These results are strong evidence that balancing selection has shaped the pattern of variation in CCR5 and suggest that HIV-1 resistance afforded by CCR5 5' cis-regulatory region haplotypes may be the consequence of adaptive changes to older pathogens.
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PMID:A strong signature of balancing selection in the 5' cis-regulatory region of CCR5. 1214 50

The increased incidence of HIV/AIDS disease in women aged 15 - 49 years has identified the urgent need for a female-controlled, efficacious and safe vaginal topical microbicide. To meet this challenge, new topical microbicide candidates consisting of molecules or formulations that modify the genital environment (BufferGel, engineered Lactobacillus, over-the-counter lubricants), surfactants (C31D/Savvy, sodium dodecyl sulfate, sodium lauryl sulfate), polyanionic polymers (PRO 2000, beta-cyclodextrin, Carraguard, CAP, D2S, SPL-7013), proteins (cyanovirin-N, monoclonal antibodies, thromspondin-1 peptides, Pokeweed antiviral protein and others), reverse transcription inhibitors (PMPA [Tenofovir ]), UC-781, SJ-3366, DABO and thiourea) and other molecules (NCp7-specific virucides, chemokine receptor agonists/antagonists, WHI-05 and WHI-07) are currently being investigated for activity, safety and efficacy. This review will assess the development of these molecules in the context of cervicovaginal defences and the clinical failure of nonoxynol-9.
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PMID:Considerations and development of topical microbicides to inhibit the sexual transmission of HIV. 1215 Jul 3

Some congenital cytomegalovirus (CMV) infections lead to neonatal disease, whereas others have no associated sequelae. To explore a possible role for viral genes as determinants of virulence, portions of the UL144 tumor necrosis factor (TNF)-alpha-like receptor gene, the US28 beta-chemokine receptor gene, and the UL55 envelope glycoprotein B gene from 33 patients with congenital CMV infection were sequenced. Three major UL144 subtypes (A, B, and C) and 2 recombinants (A/C and A/B) were detected. Infection with the least common UL144 subtypes (A, C, A/C, and A/B) was associated with unfavorable disease outcome (P=.04). There was no association between specific subtypes of the US28 and UL55 genes and outcome (P=.864 and P=.765, respectively). Multiple genotypes (implying multiple infections) were detected in tissues from 8 of 10 autopsies. Therefore, polymorphism in the CMV-encoded TNF-alpha-like receptor appears to be associated with congenital CMV disease. Other CMV polymorphisms should be further evaluated for potential relevance to neonatal infection, transplantation, and acquired immunodeficiency syndrome-associated CMV diseases.
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PMID:Polymorphisms of the cytomegalovirus (CMV)-encoded tumor necrosis factor-alpha and beta-chemokine receptors in congenital CMV disease. 1235 54

A mutant allele of the chemokine receptor gene CCR5 bearing a 32-basepair deletion (delta 32CCR5) could increase the resistance to HIV-1 infection or delayed progression to AIDS. The frequency of this mutation is higher in Europeans than in Asians. To investigate the distribution of this polymorphism in China, 715 individuals from 11 Chinese populations were screened by PCR, including the Han and 10 other ethnic groups. The delta 32CCR5 gene was found in 16 individuals from 5 ethnic groups. All of them were heterozygous. The frequency of the mutant alleles of delta 32CCR5 is low in China and reflects (or might reflect) ancestral gene flow from Europe to Chinese ethnic groups and recent intermarriage within the ethnic groups.
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PMID:Distribution of the CCR5 gene 32-basepair deletion in 11 Chinese populations. 1237 93

The unexpected encounter between the fields of HIV and chemokines has opened new perspectives for understanding the mechanisms of AIDS pathogenesis, as well as for the development of effective therapies and vaccines. Selected chemokines act as potent natural inhibitors of HIV infection, as they bind and downmodulate chemokine receptors that serve as critical coreceptors for HIV to gain access into cells. The differential usage of the two major HIV coreceptors, CCR5 and CXCR4, determines the biological diversity among HIV variants. Most primary HIV strains use CCR5 as a coreceptor and thereby are sensitive to inhibition by the CCR5-ligand chemokines, RANTES, MIP-1alpha and MIP-1beta. The high level of expression of these proinflammatory chemokines in HIV-infected secondary lymphoid tissues may help to explain the inherently slow course of HIV disease. The crucial role played by CCR5 in the physiology of HIV infection is further attested by the near-complete resistance to HIV infection in people carrying a homozygous 32 bp deletion within the CCR5 gene (CCR5-delta32). A smaller proportion of HIV isolates, commonly emerging in concomitance with the clinical progression toward AIDS, uses CXCR4 as a coreceptor and is inhibited by the CXCR4 ligand, SDF-1. The high level of expresion of SDF-1 in the genital mucosa may help to explain the inefficient transmission of CXCR4-tropic HIV. Although chemokines or derivative-molecules could be exploited as therapeutic agents against HIV, the risk of inducing inflammatory side-effects or of interfering with the physiology of the homeostatic chemokine system represents a potential limitation. However, the ability of chemokines to block HIV infection can be uncoupled from their receptor-mediated signaling activity, thus providing a theoretical foundation for the rational design of safe and effective chemokine receptor inhibitors.
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PMID:Chemokines as natural HIV antagonists. 1246 90

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.
AIDS Res Hum Retroviruses 2002 Nov 01
PMID:Characterization of CD4-induced epitopes on the HIV type 1 gp120 envelope glycoprotein recognized by neutralizing human monoclonal antibodies. 1248 27

We previously reported that patients homozygous for a specific mutation (M280) in the chemokine receptor CX3CR1 progressed to AIDS more rapidly than those with other genotypes. This deleterious effect would predict that a cohort of prevalent patients would be depleted in M280 carriers, because these patients would have disappeared before recruitment. This hypothesis is confirmed in this new study based on the French SEROCO cohort showing that patients homozygous for the M280 allele were rare among the seroprevalent group. These results may explain the conflicting results published on the impact of CX3CR1 polymorphism in seroconverters.
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PMID:Deleterious genetic influence of CX3CR1 genotypes on HIV-1 disease progression. 1262 95

CXCR6 is a chemokine receptor and the primary coreceptor in SIV infection. A single nucleotide polymorphism 1469G-->A, results in a nonconservative change in codon 3 (CXCR6-E3K) of the N-terminus of the coreceptor. To investigate the relation between the chemokine receptor CXCR6 genotype and progression to Pneumocystis carinii pneumonia (PCP) and from PCP to death, we clinically assessed and genotyped 805 individuals from an African-American injection drug-using cohort in Baltimore, MD, USA, for this CXCR6-E3K polymorphism. The allele frequency of CXCR6-3K was high (44%) in African Americans and rare in European Americans (f<1%). Although time to AIDS and PCP was similar for all CXCR6 genotypes, the median survival time from PCP to death for the CXCR6-3E/E and CXCR6-3E/K genotype was 1.5 years compared to 3.1 years for the CXCR6-K/K genotype. Individuals homozygous or heterozygous for the CXCR6-3E allele were 5.6 times more likely to die a PCP-mediated AIDS-related death than were individuals homozygous for CXCR6-3K. This study shows an association between CXCR6 genotype and progression from PCP to death among African-Americans with HIV. We suggest that CXCR6 may play a role in late-stage HIV-1 infection and may alter the progression to death after initial infection with PCP.
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PMID:Genetic influence of CXCR6 chemokine receptor alleles on PCP-mediated AIDS progression among African Americans. 1276 59

The outcome of HIV-1 infection is highly variable: not all individuals exposed to HIV-1 will become infected, and among individuals who do become infected, the time from seroconversion to AIDS diagnosis is highly variable. Some patients may develop AIDS within 3 years, whereas others may remain asymptomatic for over 15 years. The reasons for these differences are not fully understood, but are thought to reflect the complex interactions between virus and host. In recent years, an important role for host genetic factors in the pathogenesis of HIV-1 infection has increasingly been appreciated. Many novel genetic polymorphisms have been identified and analyzed for their role in HIV-1 transmission and disease progression. In this review, we will give an update of the current knowledge on the role of such polymorphisms in HIV-1 disease. As recent research in this field has focussed on polymorphisms in chemokine and chemokine receptor genes, this will be the main theme of our review.
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PMID:Host genetic factors in the clinical course of HIV-1 infection: chemokines and chemokine receptors. 1281 Oct 24

The chemokine receptors CCR5 and CXCR4 serve as the cellular receptors in conjunction with CD4 for HIV-1 entry and infection of target cells. Although the virus has subverted these molecules for its own use, their natural function is to respond to activation and migration signals delivered by extracellular chemokines. A principal research objective of our laboratory is to understand the consequences of virus-chemokine receptor interactions for cellular function, as well as for entry and infection. We hypothesized that CXCR4-using (X4) and CCR5-using (R5) HIV-1 strains might elicit signals through the chemokine receptors that result in aberrant function and/or regulate virus entry or postentry steps of infection. We have focused on primary human macrophages, which express both CXCR4 and CCR5, because macrophages are a principal target for HIV-1 in vivo, inappropriate macrophage activation appears to play a major role in the pathogenesis of certain sequelae of AIDS, such as HIV encephalopathy, and macrophage infection is regulated at several steps subsequent to entry in ways that are linked to envelope- receptor interactions. This review summarizes our recent findings regarding the mechanisms of chemokine-receptor signaling in macrophages, the role of viral envelope glycoproteins in eliciting macrophage signals, and how these activation pathways may participate in macrophage infection and affect cell functions apart from infection.
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PMID:HIV-1 gp120 chemokine receptor-mediated signaling in human macrophages. 1285 73


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