Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0021051 (immunodeficiency)
71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To test the hypothesis that some subtypes of human immunodeficiency virus type 1 (HIV-1), especially subtype E, are more likely to infect mature Langerhans cells (mLC), we titrated a panel of 26 primary HIV-1 isolates of subtypes A through F on peripheral blood mononuclear cells (PBMC) and mLC. The majority of HIV-1 isolates from heterosexually infected patients did not show a preferred tropism for mLC compared to homosexually transmitted HIV-1 isolates. Only 6 of 26 isolates, 2 from patients infected by homosexual contact and 4 from patients infected by heterosexual contact, showed a higher infectivity for mLC than for PBMC. Both syncytium-inducing and non-syncytium-inducing isolates were able to infect mLC which express mRNA for the chemokine receptors CCR3, CCR5, and CXCR4.
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PMID:Langerhans cell tropism of human immunodeficiency virus type 1 subtype A through F isolates derived from different transmission groups. 931 96

Unique among known human herpesviruses, Kaposi's sarcoma-associated herpesvirus (KSHV or HHV-8) encodes chemokine-like proteins (vMIP-I and vMIP-II). vMIP-II was shown to block infection of human immunodeficiency virus-type 1 (HIV-1) on a CD4-positive cell line expressing CCR3 and to a lesser extent on one expressing CCR5, whereas both vMIP-I and vMIP-II partially inhibited HIV infection of peripheral blood mononuclear cells. Like eotaxin, vMIP-II activated and chemoattracted human eosinophils by way of CCR3. vMIP-I and vMIP-II, but not cellular MIP-1alpha or RANTES, were highly angiogenic in the chorioallantoic assay, suggesting a possible pathogenic role in Kaposi's sarcoma.
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PMID:Angiogenic and HIV-inhibitory functions of KSHV-encoded chemokines. 957 77

Entry of the type 1 human immunodeficiency virus into most cells requires the presence of the CD4 protein in combination with one of several recently described co-receptors. CXCR-4 (fusin) was the first identified, and it serves as co-receptor for T-cell-line tropic (T-tropic) HIV-1 isolates. To determine the expression of CXCR-4 in the brain, a major target of HIV pathology, we used immunohistochemistry and reverse transcriptase polymerase chain reaction with CXCR-4-specific antibodies and probes. We found that CXCR-4 was expressed in several cell types in brain, but notably in neurons and microglia, a finding that was replicated in tissue culture. The study of the expression of CXCR-4 in the brain, which may be one of many chemokine receptors in the central nervous system, may provide further insight into the interactions between brain cells, pathogens, and the immune system, and help understand the pathogenesis of HIV dementia.
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PMID:CXCR-4 (Fusin), a co-receptor for the type 1 human immunodeficiency virus (HIV-1), is expressed in the human brain in a variety of cell types, including microglia and neurons. 932 37

An animal model was used to assess whether resistance to superinfection by human immunodeficiency virus (HIV) can exist in vivo. Asymptomatic baboons (Papio cynocephalus), previously infected with HIV-2, were first challenged with homologous virus (HIV-2UC2 or HIV-2UC14) and later with heterologous virus (HIV-2UC12). After both virus inoculations, either resistance to viral infection or a transient viremia was observed. The original virus was recovered in 3 baboons, suggesting that reactivation of a latent infection occurred on heterologous challenge and that HIV-2 superinfection is blocked by processes established during prior infection. Antibody titers measured by ELISA and virus neutralization remained at low levels. However, suppression of HIV-1 replication was observed with CD8 T cells and filtered cell culture supernatants. The soluble factor involved was not a beta-chemokine. This resistance to HIV superinfection appears to be mediated at least in part by CD8 T cells that suppress virus production.
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PMID:Superinfection with human immunodeficiency virus type 2 can reactivate virus production in baboons but is contained by a CD8 T cell antiviral response. 933 53

The chemokine receptors CCR-5 and CXCR-4, and possibly CCR-3, are the principal human immunodeficiency virus type 1 (HIV-1) coreceptors, apparently interacting with HIV-1 envelope, in association with CD4. Cell lines coexpressing CD4 and these chemokine receptors were infected with a panel of seven primary HIV-2 isolates passaged in peripheral blood mononuclear cells (PBMC) and three laboratory HIV-2 strains passaged in T-cell lines. The CCR-5, CCR-3, and CXCR-4 coreceptors could all be used by HIV-2. The ability to use CXCR-4 represents a major difference between HIV-2 and the closely related simian immunodeficiency viruses. Most HIV-2 strains using CCR-5 could also use CCR-3, sometimes with similar efficiencies. As observed for HIV-1, the usage of CCR-5 or CCR-3 was observed principally for HIV-2 strains derived from asymptomatic individuals, while HIV-2 strains derived from AIDS patients used CXCR-4. However, there were several exceptions, and the patterns of coreceptor usage seemed more complex for HIV-2 than for HIV-1. The two T-tropic HIV-2 strains tested used CXCR-4 and not CCR-5, while T-tropic HIV-1 can generally use both. Moreover, among five primary HIV-2 strains all unable to use CXCR-4, three could replicate in CCR-5-negative PBMC, which has not been reported for HIV-1. These observations suggest that the CCR-5 coreceptor is less important for HIV-2 than for HIV-1 and indicate that HIV-2 can use other cell entry pathways and probably other coreceptors. One HIV-2 isolate replicating in normal or CCR-5-negative PBMC failed to infect CXCR-4+ cells or the U87MG-CD4 and sMAGI cell lines, which are permissive to infection by HIV-2 but not by HIV-1. This suggests the existence of several HIV-2-specific coreceptors, which are differentially expressed in cell lines and PBMC.
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PMID:Usage of the coreceptors CCR-5, CCR-3, and CXCR-4 by primary and cell line-adapted human immunodeficiency virus type 2. 934 75

The CC chemokine receptors CCR5, CCR2, and CCR3 and the CXC chemokine receptor CXCR4 have been implicated as CD4-associated cofactors in the entry of primary and cell line-adapted human immunodeficiency virus type 1 (HIV-1) strains. CXCR4 is also a receptor for T-cell-line-adapted, CD4-independent strains of HIV-2. With the exception of this latter example, little has been reported on the entry cofactors used by HIV-2 strains. Here we show that a CD4-dependent, T-cell-line-adapted HIV-2 strain uses CXCR4 and, to a lesser extent, CCR3 for fusion with and infectious entry into cells. In a cell-to-cell fusion assay, the envelope protein of this virus can utilize a wider repertoire of chemokine receptors to induce fusion. These include CCR1, CCR2, CCR3, CCR4, CCR5, CXCR2, and CXCR4. Kinetic analysis indicated that cell lines expressing the receptors that support infection, CXCR4 and CCR3, form syncytia more rapidly than do cell lines expressing the other receptors. Nevertheless, although less efficient, fusion with CXCR2 expressing cells was specific, since it was inhibited by antibodies against CXCR2. The extensive use of chemokine receptors in cell-to-cell fusion has implications for understanding the molecular basis of CD4-chemokine receptor-induced lentivirus fusion and may have relevance for syncytium formation and the direct cell-to-cell transfer of virus in vivo.
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PMID:Promiscuous use of CC and CXC chemokine receptors in cell-to-cell fusion mediated by a human immunodeficiency virus type 2 envelope protein. 934 97

CCR5, a receptor for the CC chemokines RANTES, Mip1alpha, and Mip1beta, has been identified as a coreceptor for infections by macrophage-tropic isolates of human immunodeficiency virus type 1 (HIV-1). To study its structure and function, we isolated cDNA clones of human, African green monkey (AGM), and NIH/Swiss mouse CCR5s, and we quantitatively analyzed infections by macrophage-tropic HIV-1 and SIVmac251 after transfecting human HeLa-CD4 cells with the CCR5 expression vectors. The AGM and NIH/Swiss mouse CCR5 proteins are 97.7 to 98.3% and 79.8% identical to the human protein, respectively. In addition, we analyzed site-directed mutants and chimeras of these CCR5s. Cell surface expression of CCR5 proteins was monitored by using a specific rabbit antiserum and by binding the chemokine [125I]Mip1beta. Our major results were as follows. (i) Two distinct AGM CCR5 sequences were reproducibly found in DNA from CV-1 cells. The AGM clone 1 CCR5 protein differs from that of clone 2 by two substitutions, Y14N in the amino-terminal extracellular region and L352F at the carboxyl terminus. Interestingly, AGM clone 1 CCR5 was inactive as a coreceptor for all tested macrophage-tropic isolates of HIV-1, whereas AGM clone 2 CCR5 was active. As shown by chimera studies and site-directed mutagenesis, the Y14N substitution in AGM clone 1 CCR5 was solely responsible for blocking HIV-1 infections. In contrast, both AGM CCR5 clones were active coreceptors for SIVmac251. Studies of DNA samples from other AGMs indicated frequent additional CCR5 polymorphisms, and we cloned an AGM clone 2 variant with a Q93R substitution in the extracellular loop 1 from one heterozygote. This variant CCR5 was active as a coreceptor for SIVmac251 but was only weakly active for macrophage-tropic isolates of HIV-1. In addition, SIVmac251 appeared to be dependent on the extracellular amino terminus and loop 2 regions of human CCR5 for maximal infection. Our results suggest major differences in the interactions of SIVmac251 and macrophage-tropic HIV-1 isolates with 19, N13, and Y14 in the amino terminus; with Q93 in extracellular loop 1; and with extracellular loop 2 of human CCR5. (ii) The NIH/Swiss mouse CCR5 protein differs at multiple positions from sequences recently reported for other inbred strains of mice. This CCR5 was inactive as a coreceptor for HIV-1 and SIVmac251. Studies of chimeras that contained different portions of NIH/Swiss mouse CCR5 substituted into human CCR5, as well as the reciprocal chimeras, indicated that the amino-terminal region and extracellular loops 1 and 2 of human CCR5 contribute to its coreceptor activity for macrophage-tropic isolates of HIV-1. Specific differences with previous CCR5 chimera results occurred because the NIH/Swiss mouse CCR5 contains a unique substitution corresponding to P183L in extracellular loop 2 that is nonpermissive for coreceptor activity. We conclude that diverse CCR5 sequences occur in AGMs and mice, that SIVmac251 and macrophage-tropic HIV-1 isolates interact differently with specific CCR5 amino acids, and that multiple regions of human CCR5 contribute to its coreceptor functions. In addition, we have identified naturally occurring amino acid polymorphisms in three extracellular regions of CCR5 (Y14N, Q93R, and P183L) that do not interfere with cell surface expression or Mip1beta binding but prevent infections by macrophage-tropic isolates of HIV-1. In contrast to previous evidence, these results suggest that CCR5 contains critical sites that are essential for HIV-1 infections.
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PMID:Polymorphisms in the CCR5 genes of African green monkeys and mice implicate specific amino acids in infections by simian and human immunodeficiency viruses. 934 22

The chemokine receptor CXCR4 is required, together with CD4, for entry by some isolates of HIV-1, particularly those that emerge late in infection. The use of CXCR4 by these viruses likely has profound effects on viral host range and correlates with the evolution of immunodeficiency. Stromal cell-derived factor-1 (SDF-1), the ligand for CXCR4, can inhibit infection by CXCR4-dependent viruses. To understand the mechanism of this inhibition, we used a monoclonal antibody that is specific for CXCR4 to analyze the effects of phorbol esters and SDF-1 on surface expression of CXCR4. On human T cell lines SupT1 and BC7, CXCR4 undergoes slow constitutive internalization (1.0% of the cell surface pool/min). Addition of phorbol esters increased this endocytosis rate >6-fold and reduced cell surface CXCR4 expression by 60 to 90% over 120 min. CXCR4 was internalized through coated pits and coated vesicles and subsequently localized in endosomal compartments from where it could recycle to the cell surface after removal of the phorbol ester. SDF-1 also induced the rapid down modulation (half time approximately 5 min) of CXCR4. Using mink lung epithelial cells expressing CXCR4 and a COOH-terminal deletion mutant of CXCR4, we found that an intact cytoplasmic COOH-terminal domain was required for both PMA and ligand-induced CXCR4 endocytosis. However, experiments using inhibitors of protein kinase C indicated that SDF-1 and phorbol esters trigger down modulation through different cellular mechanisms. SDF-1 inhibited HIV-1 infection of mink cells expressing CD4 and CXCR4. The inhibition of infection was less efficient for CXCR4 lacking the COOH-terminal domain, suggesting at least in part that SDF-1 inhibition of virus infection was mediated through ligand-induced internalization of CXCR4. Significantly, ligand induced internalization of CXCR4 but not CD4, suggesting that CXCR4 and CD4 do not normally physically interact on the cell surface. Together these studies indicate that endocytosis can regulate the cell-surface expression of CXCR4 and that SDF-1-mediated down regulation of cell-surface coreceptor expression contributes to chemokine-mediated inhibition of HIV infection.
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PMID:Phorbol esters and SDF-1 induce rapid endocytosis and down modulation of the chemokine receptor CXCR4. 934 82

Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) enter target cells by forming a complex between the viral envelope protein and two cell-surface membrane receptors: CD4 and a 7-span transmembrane chemokine receptor. Isolates of HIV that differ in cellular tropism use different subsets of chemokine receptors as entry cofactors: macrophage-tropic HIVs primarily use CCR5, whereas T-cell-tropic and dual-tropic isolates use CXCR4 receptors. HIV-mediated signal transduction through CCR5 is not required for efficient fusion and entry of HIV in vitro. Here we show that recombinant envelope proteins from macrophage-tropic HIV and SIV induce a signal through CCR5 on CD4+ T cells and that envelope-mediated signal transduction through CCR5 induces chemotaxis of T cells. This chemotactic response may contribute to the pathogenesis of HIV in vivo by chemo-attracting activated CD4+ cells to sites of viral replication. HIV-mediated signalling through CCR5 may also enhance viral replication in vivo by increasing the activation state of target cells. Alternatively, envelope-mediated CCR5 signal transduction may influence viral-associated cytopathicity or apoptosis.
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PMID:Macrophage-tropic HIV and SIV envelope proteins induce a signal through the CCR5 chemokine receptor. 935 23

Following the identification of the C-C chemokines RANTES, MIP-1alpha and MIP-1beta as major human immunodeficiency virus (HIV)-suppressive factors produced by CD8+ T cells, several chemokine receptors were found to serve as membrane co-receptors for primate immunodeficiency lentiretroviruses. The two most widely used co-receptors thus far recognized, CCR5 and CXCR4, are expressed by both activated T lymphocytes and mononuclear phagocytes. CCR5, a specific RANTES, MIP-1alpha and MIP-1 receptor, is used preferentially by non-MT2-tropic HIV-1 and HIV-2 strains and by simian immunodeficiency virus (SIV), whereas CXCR4, a receptor for the C-X-C chemokine SDF-1, is used by MT2-tropic HIV-1 and HIV-2, but not by SIV. Other receptors with a more restricted cellular distribution, such as CCR2b, CCR3 and STRL33, can also function as co-receptors for selected viral isolates. The third variable region (V3) of the gp120 envelope glycoprotein of HIV-1 has been fingered as a critical determinant of the co-receptor choice. Here, we document a consistent pattern of evolution of viral co-receptor usage and sensitivity to chemokine-mediated suppression in a longitudinal follow-up of children with progressive HIV-1 infection. Viral isolates obtained during the asymptomatic stages generally used only CCR5 as a co-receptor and were inhibited by RANTES, MIP-1alpha and MIP-1beta, but not by SDF-1. By contrast, the majority of the isolates derived after the progression of the disease were resistant to C-C chemokines, having acquired the ability to use CXCR4 and, in some cases, CCR3, while gradually losing CCR5 usage. Surprisingly, most of these isolates were also insensitive to SDF-1, even when used in combination with RANTES. An early acquisition of CXCR4 usage predicted a poor prognosis. In children who progressed to AIDS without a shift to CXCR4 usage, all the sequential isolates were CCR5-dependent but showed a reduced sensitivity to C-C chemokines. Discrete changes in the V3 domain of gp120 were associated with the loss of sensitivity to C-C chemokines and the shift in co-receptor usage. These results suggest an adaptive evolution of HIV-1 in vivo, leading to escape from the control of the antiviral C-C chemokines.
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PMID:In vivo evolution of HIV-1 co-receptor usage and sensitivity to chemokine-mediated suppression. 935 2


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