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)

We have analyzed the unique epitope for the broadly neutralizing human monoclonal antibody (MAb) 2G12 on the gp120 surface glycoprotein of human immunodeficiency virus type 1 (HIV-1). Sequence analysis, focusing on the conservation of relevant residues across multiple HIV-1 isolates, refined the epitope that was defined previously by substitutional mutagenesis (A. Trkola, M. Purtscher, T. Muster, C. Ballaun, A. Buchacher, N. Sullivan, K. Srinivasan, J. Sodroski, J. P. Moore, and H. Katinger, J. Virol. 70:1100-1108, 1996). In a biochemical study, we digested recombinant gp120 with various glycosidase enzymes of known specificities and showed that the 2G12 epitope is lost when gp120 is treated with mannosidases. Computational analyses were used to position the epitope in the context of the virion-associated envelope glycoprotein complex, to determine the variability of the surrounding surface, and to calculate the surface accessibility of possible glycan- and polypeptide-epitope components. Together, these analyses suggest that the 2G12 epitope is centered on the high-mannose and/or hybrid glycans of residues 295, 332, and 392, with peripheral glycans from 386 and 448 on either flank. The epitope is mannose dependent and composed primarily of carbohydrate, with probably no direct involvement of the gp120 polypeptide surface. It resides on a face orthogonal to the CD4 binding face, on a surface proximal to, but distinct from, that implicated in coreceptor binding. Its conservation amidst an otherwise highly variable gp120 surface suggests a functional role for the 2G12 binding site, perhaps related to the mannose-dependent attachment of HIV-1 to DC-SIGN or related lectins that facilitate virus entry into susceptible target cells.
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PMID:The mannose-dependent epitope for neutralizing antibody 2G12 on human immunodeficiency virus type 1 glycoprotein gp120. 1207 28

Chemokines have received increasing attention due to their inhibitory activities on human immunodeficiency virus type-1 (HIV-1) and simian immunodeficiency virus (SIV) replication and the potential for chemokine receptors to assist in HIV-1/SIV entry into permissive cells. Besides CD4, which is the major receptor for HIV-1 and SIV, a number of chemokine receptors including but not limited to APJ, CCR3, CXCR4, and CCR5 may be coreceptors for HIV-1/SIV, not only in peripheral blood and lymphoid tissues but also in the central nervous system (CNS). The present studies reveal the lack of CD4, but the significant expression of various chemokine receptors, APJ, CCR3, CXCR4, and CCR5, plus C-type lectins DC-SIGN and L-SIGN on isolated primary human brain microvascular endothelial cells (MVECs). As these MVECs do not express CD4, this suggests a CD4-independent HIV/SIV entry/infection of these cells, which are the major cells constituting the human blood-brain barrier. We also found that chemokines for cognate chemokine receptors individually were unable to block binding of HIV-1 to brain MVECs. These results reveal that in primary isolated brain MVECs viral attachment is mediated by a possible previously unknown receptor(s) or by cooperative activity of various receptors. Moreover, mRNA transcripts for DC-SIGN/L-SIGN, as well as DC-SIGN protein expression, suggest the capability of MVECs to attach viral particles on cell surfaces, even though polyclonal antisera for DC-SIGN did not affect viral binding to these cells. These data will assist in further understanding lentiviral entry into the CNS.
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PMID:Primary isolated human brain microvascular endothelial cells express diverse HIV/SIV-associated chemokine coreceptors and DC-SIGN and L-SIGN. 1208 38

Dendritic cells (DC) support human immunodeficiency virus type 1 (HIV-1) transmission by capture of the virus particle in the mucosa and subsequent transport to the draining lymph node, where HIV-1 is presented to CD4(+) Th cells. Virus transmission involves a high-affinity interaction between the DC-specific surface molecule DC-SIGN and the viral envelope glycoprotein gp120 and subsequent internalization of the virus, which remains infectious. The mechanism of viral transmission from DC to T cells is currently unknown. Sentinel immature DC (iDC) develop into Th1-promoting effector DC1 or Th2-promoting DC2, depending on the activation signals. We studied the ability of these effector DC subsets to support HIV-1 transmission in vitro. Compared with iDC, virus transmission is greatly upregulated for the DC1 subset, whereas DC2 cells are inactive. Increased transmission by DC1 correlates with increased expression of ICAM-1, and blocking studies confirm that ICAM-1 expression on DC is important for HIV transmission. The ICAM-1-LFA-1 interaction is known to be important for immunological cross talk between DC and T cells, and our results indicate that this cell-cell contact is exploited by HIV-1 for efficient transmission.
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PMID:Differential transmission of human immunodeficiency virus type 1 by distinct subsets of effector dendritic cells. 1209 93

DC-SIGNR is a human immunodeficiency virus (HIV)-binding C-type lectin that is expressed on endothelium in the hepatic sinusoids, lymph node sinuses and placenta. Like closely related DC-SIGN, DC-SIGNR can bind both ICAM-3 and HIV and can potentiate HIV infection of T lymphocytes in trans. In the present study we have investigated reasons underlying the restricted distribution of DC-SIGNR and have examined DC-SIGNR expression in relation to HIV entry receptors. We show that DC-SIGNR expression does not depend on endothelial cell specialization or on activation state. DC-SIGNR-positive endothelium continues to express DC-SIGNR in conditions of hyperplasia, whereas the molecule is lost after neoplastic transformation, most likely as a result of changes in the microenvironment of the endothelial cells. We have further shown that CCR5, but not CD4, is coexpressed with DC-SIGNR on hepatic sinusoidal and placental capillary endothelial cells. However, CD4-positive CCR5-positive cells, such as hepatic Kupffer cells, placental Hofbauer cells, and CD4-positive T lymphocytes in lymph nodes, can be found adjacent to DC-SIGNR-positive endothelium. Therefore, DC-SIGNR may be able to mediate HIV infection of these cells in trans. Finally, we demonstrate that DC-SIGN and DC-SIGNR can be coexpressed on lymph node sinus endothelial cells, which may lead to modulation of the function of both molecules.
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PMID:Expression of human immunodeficiency virus (HIV)-binding lectin DC-SIGNR: Consequences for HIV infection and immunity. 1215 66

The dendritic cell (DC)-specific molecule DC-SIGN is a receptor for the HIV-1 envelope glycoprotein gp120 and is essential for the dissemination of HIV-1. DC-SIGN is expressed by DCs, both monocyte-derived DCs and DCs in several tissues, including mucosa and lymph nodes. To identify a DC-SIGN(+) DC in blood that may be involved in HIV-1 infection through blood, we have analyzed the expression of DC-SIGN in human blood cells. Here we describe the characterization of a subset of DCs in human blood, isolated from T-/NK-/B-cell-depleted peripheral blood mononuclear cells (PBMCs) on the basis of expression of DC-SIGN. This subset coexpresses CD14, CD16, and CD33 and is thus of myeloid origin. In contrast to CD14(+) monocytes, DC-SIGN(+) blood cells display a DC-like morphology and express markers of antigen-presenting cells, including CD1c, CD11b, CD11c, CD86, and high levels of major histocompatibility complex (MHC) class I and II molecules. This DC population differs from other described CD14(-) blood DC subsets. Functionally, DC-SIGN(+) blood DCs are able to stimulate proliferation of allogeneic T cells and can produce tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) upon activation with lipopolysaccharide (LPS). When they encounter HIV-1, low amounts of these blood DC-SIGN(+) DCs enhance infection of T lymphocytes in trans, whereas blood monocytes and CD14(-) blood DCs are not capable of transmitting HIV-1. Therefore DC-SIGN(+) blood DCs can be the first target for HIV-1 upon transmission via blood; they can capture minute amounts of HIV-1 through DC-SIGN and transfer HIV-1 to infect target T cells in trans.
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PMID:Subset of DC-SIGN(+) dendritic cells in human blood transmits HIV-1 to T lymphocytes. 1217

During sexual transmission of HIV, virus crosses mucosal epithelium and eventually reaches lymphoid tissue where it establishes a permanent infection. Evidence has accumulated that infection of Langerhans cells, which are resident dendritic cells in pluristratified epithelia, plays a crucial role in the early events of HIV transmission. HIV infection of Langerhans cells is regulated by surface expression of CD4 and CCR5. Thus, topical microbicides that interfere with HIV infection of Langerhans cells represent an attractive strategy for blocking sexual transmission of virus. Capture and uptake of HIV virions is another major pathway by which HIV interacts with dendritic cells. By contrast, this process is mediated by a newly described C-type lectin, DC-SIGN. It is well established that HIV-exposed dendritic cells transmit virus efficiently to cocultured T cells. Indeed, dendritic cell-T cell interaction, critical in the generation of immune responses, is a rich microenvironment for HIV replication both in vitro and in vivo. Dendritic cells that have captured virus via DC-SIGN, and not HIV-infected dendritic cells, probably facilitate most infection of T cells in chronically infected individuals. Therefore, blocking DC-SIGN-mediated capture of HIV represents a potential therapeutic antiviral strategy for HIV disease. Lastly, dendritic cells have been targeted both ex vivo and in vivo to initiate and enhance HIV-specific immunity. Although these approaches are promising for both therapeutic and prophylactic vaccines, much additional work is needed in order to optimize dendritic-cell-based immunization strategies.
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PMID:Essential roles for dendritic cells in the pathogenesis and potential treatment of HIV disease. 1219 Aug 58

Sexual transmission of HIV requires that the virus crosses mucosal barriers and disseminates into lymphoid tissue, the major site of viral replication. To achieve this, HIV might engage DC-SIGN, a calcium dependent lectin that is expressed on mucosal dendritic cells (DCs), which binds avidly to HIV. DC-SIGN and other attachment factors are likely to account for the well-known ability of DCs to enhance infection of T cells by HIV. Attachment of HIV to DC-SIGN might thus enhance viral spread in mucosal tissues and, by taking advantage of the inherent capacity of DCs to migrate into lymphoid tissue, might promote viral dissemination within the host. DC-SIGN and a related molecule, termed DC-SIGNR, also enhance infection by Ebola virus. The expression of these lectins on early targets of Ebola virus infection, like liver endothelial cells and alveolar macrophages, suggests an important role for DC-SIGN and DC-SIGNR in the establishment of Ebola infection. This article reviews the interaction of DC-SIGN and DC-SIGNR with HIV and Ebola, discusses the mechanism of DC-SIGN-mediated viral transmission and examines how this process could be inhibited by potential therapeutics.
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PMID:The role of DC-SIGN and DC-SIGNR in HIV and Ebola virus infection: can potential therapeutics block virus transmission and dissemination? 1222 58

We report here the gene for DC-SIGN from Chinese rhesus macaques. DC-SIGN is a C-type lectin expressed by dendritic cells (DCs). It is involved in the interaction of DCs with T cells, and in transmission to T cells of HIV-1 and SIV. Alternative splicing in human DC-SIGN yields A and B isoforms of the protein. The overall organization of the rhesus macaque gene is similar to that of the human gene. Translation of B isoforms cannot occur because of a point substitution. The coding sequence shows that we have cloned a fourth allele for rhesus macaque DC-SIGN. This allele shows high homology to the other rhesus macaque alleles. However, at the protein level, the homology is highest with the pigtail macaque protein. This suggests a convergent evolution of DC-SIGN in macaques living in China. The importance of DC-SIGN variability in the immune response remains to be investigated.
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PMID:Gene for chinese rhesus macaque DC-SIGN predicts the existence of A but not B isoforms of the protein. 1223 Sep 40

Dendritic cell (DC)-specific ICAM-3 grabbing nonintegrin (DC-SIGN) is a DC-specific antigen that plays an important role in the induction of primary immune responses as well as during HIV infection. In the present study, we analyzed the effect of binding of monoclonal antibody DCN46 to DC surface, expressed DC-SIGN on DC function. DC-SIGN antibody treated, immature DC were able to differentiate into mature DC and had the same capacity as untreated DC to induce primary and secondary immune responses. In combination with flow cytometric cell sorting, DC-SIGN antibody treatment of DC yielded highly pure and functional DC. Given the apparent lack of functional effect of monoclonal antibody DCN46 on DC, the latter antibody may prove useful for research on and clinical use of highly pure and functional DC.
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PMID:Functional aspects of binding of monoclonal antibody DCN46 to DC-SIGN on dendritic cells. 1227 May 46

The ability of HIV-1 to use dendritic cells (DCs) for transport and to transfer virus to activated T cells in the lymph node may be crucial in early HIV-1 pathogenesis. We have characterized primary DCs for the receptors involved in viral envelope attachment and observed that C-type lectin receptor (CLR) binding was predominant in skin DCs, whereas binding to emigrating and tonsil DCs was CD4-dependent. No one CLR was solely responsible for envelope binding on all skin DC subsets. DC-SIGN (DC-specific ICAM-3-grabbing nonintegrin) was only expressed by CD14(+)CDla(lo) dermal DCs. The mannose receptor was expressed by CD1a(hi) and CD14(+)CDla(lo) dermal DCs, and langerin was expressed by Langerhans cells. The diversity of CLRs able to bind HIV-1 in skin DCs may reflect their ability to bind a range of microbial glycoproteins.
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PMID:Diversity of receptors binding HIV on dendritic cell subsets. 1235 61


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