Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Here we report that the N-pyridinylmethyl cyclam analog AMD3451 has antiviral activity against a wide variety of R5, R5/X4, and X4 strains of human immunodeficiency virus type 1 (HIV-1) and HIV-2 (50% inhibitory concentration [IC(50)] ranging from 1.2 to 26.5 microM) in various T-cell lines, CCR5- or CXCR4-transfected cells, peripheral blood mononuclear cells (PBMCs), and monocytes/macrophages. AMD3451 also inhibited R5, R5/X4, and X4 HIV-1 primary clinical isolates in PBMCs (IC(50), 1.8 to 7.3 microM). A PCR-based viral entry assay revealed that AMD3451 blocks R5 and X4 HIV-1 infection at the virus entry stage. AMD3451 dose-dependently inhibited the intracellular Ca(2+) signaling induced by the CXCR4 ligand CXCL12 in T-lymphocytic cells and in CXCR4-transfected cells, as well as the Ca(2+) flux induced by the CCR5 ligands CCL5, CCL3, and CCL4 in CCR5-transfected cells. The compound did not interfere with chemokine-induced Ca(2+) signaling through CCR1, CCR2, CCR3, CCR4, CCR6, CCR9, or CXCR3 and did not induce intracellular Ca(2+) signaling by itself at concentrations up to 400 microM. In freshly isolated monocytes, AMD3451 inhibited the Ca(2+) flux induced by CXCL12 and CCL4 but not that induced by CCL2, CCL3, CCL5, and CCL7. The CXCL12- and CCL3-induced chemotaxis was also dose-dependently inhibited by AMD3451. Furthermore, AMD3451 inhibited CXCL12- and CCL3L1-induced endocytosis in CXCR4- and CCR5-transfected cells. AMD3451, in contrast to the specific CXCR4 antagonist AMD3100, did not inhibit but enhanced the binding of several anti-CXCR4 monoclonal antibodies (such as clone 12G5) at the cell surface, pointing to a different interaction with CXCR4. AMD3451 is the first low-molecular-weight anti-HIV agent with selective HIV coreceptor, CCR5 and CXCR4, interaction.
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PMID:Inhibition of human immunodeficiency virus replication by a dual CCR5/CXCR4 antagonist. 1554 51

Segmental duplications in the human genome are selectively enriched for genes involved in immunity, although the phenotypic consequences for host defense are unknown. We show that there are significant interindividual and interpopulation differences in the copy number of a segmental duplication encompassing the gene encoding CCL3L1 (MIP-1alphaP), a potent human immunodeficiency virus-1 (HIV-1)-suppressive chemokine and ligand for the HIV coreceptor CCR5. Possession of a CCL3L1 copy number lower than the population average is associated with markedly enhanced HIV/acquired immunodeficiency syndrome (AIDS) susceptibility. This susceptibility is even greater in individuals who also possess disease-accelerating CCR5 genotypes. This relationship between CCL3L1 dose and altered HIV/AIDS susceptibility points to a central role for CCL3L1 in HIV/AIDS pathogenesis and indicates that differences in the dose of immune response genes may constitute a genetic basis for variable responses to infectious diseases.
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PMID:The influence of CCL3L1 gene-containing segmental duplications on HIV-1/AIDS susceptibility. 1574 16

Several genetic factors influence HIV-1 susceptibility or AIDS disease progression. A recent study reported on what could be a particularly important genetic determinant for HIV-1 susceptibility and disease progression: copy number of a chemokine gene termed CCL3L1. Individuals with low copy numbers of the gene, relative to their ethnic background, were associated with markedly enhanced HIV-1/AIDS susceptibility. These findings define an important new genetic determinant of HIV-1 susceptibility and further emphasize the importance of the chemokine system, either as elements that inhibit HIV-1 infection or that modulate antiviral immune responses.
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PMID:CCL3L1 dose and HIV-1 susceptibility. 1588 7

Susceptibility to HIV-1 infections is, beside other factors, determined by individual host genetic variants like HLA class I alleles, CCR5 and CCR2 variants and levels of CCR5 binding chemokines. A new approach to determine the individual risk of acquiring an HIV infection or to estimate the disease progression could now be possible. In a recent study, a significant interindividual and interpopulation difference in the copy number of a segmental duplication encompassing the gene encoding CCL3L1, a potent human immunodeficiency virus-1 (HIV- 1)-suppressive chemokine was found. Possession of a CCL3L1 copy number lower than the population average was associated with markedly enhanced HIV/acquired immunodeficiency syndrome (AIDS) susceptibility. This could lead to a screening test that identifies people who have a higher or lower susceptibility to HIV/ AIDS, potentially enabling clinicians to adapt treatment regimens. Also, this is particularly important for assessment of the efficacy of a protective vaccine.
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PMID:Susceptibility to HIV/AIDS: an individual characteristic we can measure? 1594 Apr 20

Susceptibility to HIV infection and AIDS progression is variable among individuals and populations, and in part genetically determined. Genetic variants of genes encoding HIV co-receptors and their chemokine ligands have been described, and some of these variants were associated with resistance to HIV infection and/or disease progression. We review here the reported data regarding the variants of the CCR5, CCR2, CX3CR1, MIP-1alpha/CCL3, MIP-1beta/CCL4, RANTES/CCL5 and SDF-1/CXCL12 genes. The Delta32 deletion mutant of CCR5, resulting in a non-functional receptor not reaching the cell surface, is unambiguously associated with strong, although incomplete, resistance to HIV infection for homozygotes, and retarded progression for heterozygotes. Specific haplotypes encompassing the CCR5 and CCR2 loci, and the copy number of the CCL3L1 gene, have also been convincingly correlated with delayed progression. For other gene variants, involving CXCL12/SDF-1 and CX3CR1, conclusive evidence for their relevance in the frame of HIV susceptibility is still lacking.
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PMID:Genetics of resistance to HIV infection: Role of co-receptors and co-receptor ligands. 1697 74

HIV infection is the serious medical and public health issue of present generation. By 2005, it has already infected a cumulative total of more than sixty million people worldwide and the number of HIV positive cases are rising day by day. India is currently estimated to have about 5.1 million infected persons with HIV-1 or AIDS (second only to South Africa) and this number could increase to 24 million in the next ten years. This pandemic situation of the AIDS stimulated a plethora of longitudinal cohort studies which are designed to document medical heterogeneity as well as to mitigate the factors that regulate the HIV-1 infection, disease progression and the immune defenses. In recent years these genetic studies have led to the discovery of various MHC and non MHC encoded genes, which directly or indirectly influence the susceptibility and resistance to HIV infection and AIDS. These genes and their mutated forms and their products which play a major role in determining the susceptibility or resistance to HIV-1 infection and AIDS. These genes have been categorized into MHC or non MHC encoded genes. The MHC encoded genes which determine HIV resistance or susceptibility are HLA-B57, HLA-B58, HLA-B27, HLA-Bw4 and HLA-A11 in Southeast Asians. On the other hand, non MHC encoded genes are CCR5, CCR2, RANTES, CXCL12, CXCR6, CCL3L1, Interleukin-10 (IL-10), and interferon gamma. The site specific mutations in these genes determine the susceptibility or resistance to HIV-1 infection and AIDS. In future the study of host genes in relation to HIV-1 infection may provide the researchers to develop newer chemotherapeutic approaches to prevent or cure HIV-1 infection effectively.
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PMID:Genetic basis of HIV-1 resistance and susceptibility: an approach to understand correlation between human genes and HIV-1 infection. 1699 22

Leukocytes of persons coinfected with HTLV-2 and HIV-1 secrete chemokines that prevent CCR5-dependent (R5) HIV-1 infection of CD4+ T cells and macrophages, with HTLV-2-induced MIP-1alpha as dominant HIV-1 inhibitory molecule. Two nonallelic genes code for CCL3 and CCL3L1 isoforms of MIP-1alpha, and the population-specific copy number of CCL3L1 exerts a profound effect on HIV-1 susceptibility and disease progression. Here, we demonstrate that CCL3L1 is secreted spontaneously by leukocytes of HTLV-2-infected persons and superinduced when cells of HTLV-2/HIV-1 multiply exposed-uninfected seronegative (MEU) persons were stimulated with HIV-1 Env peptides. The CCL3L1 median copy number in MEU, HTLV-2/HIV-1-coinfected long-term nonprogressors (LTNPs) and HIV-1-monoinfected LTNPs were 1, 2, and 3, respectively. An increased CCL3L1/CCL3 mRNA ratio versus PHA-activated healthy leukocytes was observed in both HIV-1-monoinfected LTNPs and in HTLV-2/HIV-1(MEU) subjects. An additional potential correlate of HTLV-2 infection was a rapid and persistent leukocyte secretion of GM-CSF and IFN-gamma, 2 cytokines endowed with CCR5 down-regulation capacity. This study confirms a crucial protective role of CCL3L1 from both HIV infection and disease progression, highlighting a previously not described functional up-regulation of this chemokine variant in both HIV-positive and -negative persons infected with HTLV-2.
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PMID:Postgenomic up-regulation of CCL3L1 expression in HTLV-2-infected persons curtails HIV-1 replication. 1706 25

Several CCR5 ligands, including small molecules and monoclonal antibodies (MAbs), are being developed as therapies for infection with strains of human immunodeficiency virus type 1 (HIV-1) that use CCR5 for entry (R5 viruses). The efficacy of such therapies could be influenced by inter-individual differences in host factors, such as CCR5 expression levels. To study this, we used peripheral blood mononuclear cells (PBMCs) from humans and rhesus macaques. The half-maximal inhibitory concentrations (IC(50)) of the small-molecule CCR5 ligands CMPD167, UK427,857 and SCH-D, and of the PRO 140 MAb, differ by >2 logs in a donor-dependent manner. We studied this variation by using flow cytometry to measure CCR5 expression on PBMCs from six of the human donors: the IC(50) values of both SCH-D and PRO 140 correlated with CCR5 expression (R(2)=0.64 and 0.99, respectively). We also determined the efficacy of the CCR5 ligands against HIV-1 infection of HeLa-derived cell lines that express CD4 at the same level but vary 2-fold in CCR5 expression (JC.48 and JC.53 cells). The moderately greater CCR5 expression on the JC.53 than the JC.48 cells was associated with proportionately higher median IC(50) values for all four CCR5 ligands but not for a soluble CD4-based inhibitor or a non-nucleoside reverse transcriptase inhibitor. We conclude that differences in CCR5 expression on human PBMCs, which can be affected by CCL3L1 gene dose, may influence the antiviral potency of CCR5 ligands in vitro, but other host factors are also likely to be involved. These host factors may affect the clinical activity of CCR5 inhibitors, including their use as topical microbicides to prevent HIV-1 transmission.
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PMID:Cell surface expression of CCR5 and other host factors influence the inhibition of HIV-1 infection of human lymphocytes by CCR5 ligands. 1742 18

Due to the increasing number of infections with hepatitis viruses and HIV, world wide as well as among the health care workers, the prevention of occupationally acquired infections in the operating room environment becomes crucial. Three plausible strategies do not require any knowledge of the exact mechanisms of exposure: vaccination, impenetrable protective barriers and post exposure prophylaxis. This paper presents the opinion on individual risks of HIV infections based on genetic factors. It has been proved that one of the CCR5 gene varient for chemokine receptor is related with resistance to HIV-1 infection. Similary, the level of cytokine depends on the number of gene CCL3L1 copy and it influences susceptibility to HIV-1 infection and AIDS development.
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PMID:[Evaluation of individual vulnerability to HIV infection of health care employees--hope or reality?]. 1747 73

We set up a cohort of HIV-infected, asymptomatic Japanese patients with hemophilia for follow-up study in 1995. All subjects who had been infected with HIV-1 for more than 10 years met the criteria for long-term nonprogressors (LTNPs) at the time of entry; however, some of them later developed lymphopenia and required antiretroviral treatment during five more years of observation. In this study, we investigated the impacts of the CCL3L1 dose on the long-term prognosis in the subjects with chronic HIV-1 infection. We collected genomic DNA from 95 long-term survivors including 48 nonprogressors and 47 subjects receiving antiretroviral treatment. The distributions of CCL3L1 copy number significantly differed between the 95 HIV-1-infected subjects with hemophilia and 205 controls. Average copy number of CCL3L1 in the HIV-1-infected subjects was significantly lower than in control (5.00 +/- 0.22 vs 3.35 +/- 0.24, p < 0.001). Moreover, the subjects possessing two or less copies of CCL3L1 had significantly higher risk of acquiring HIV-1. However, CCL3L1 copy number variations had no significant effect on the disease progression among the LTNP subjects who had been afflicted with chronic HIV-1 infection for more than 15 years, when compared between nonprogressors and patients under treatment (3.68 +/- 0.37 vs 3.02 +/- 0.29, ns). Furthermore, variations in the CCL3L1 copy number had little effect on the levels of HIV-1 load among them. We conclude that variation in the CCL3L1 copy number is apparently not a factor that determines the prognosis of chronic HIV-1 infection, even though it is linked to HIV-1 susceptibility.
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PMID:Copy number variations of CCL3L1 and long-term prognosis of HIV-1 infection in asymptomatic HIV-infected Japanese with hemophilia. 1787 89


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