title: Dendritic cell immunoreceptor is a new target for anti-AIDS drug development: identification of DCIR/HIV-1 inhibitors.
abstract: The HIV-1 pandemic continues to expand while no effective vaccine or cure is yet available. Existing therapies have managed to limit mortality and control viral proliferation, but are associated with side effects, do not cure the disease and are subject to development of resistance. Finding new therapeutic targets and drugs is therefore crucial. We have previously shown that the dendritic cell immunoreceptor (DCIR), a C-type lectin receptor expressed on dendritic cells (DCs), acts as an attachment factor for HIV-1 to DCs and contributes to HIV-1 transmission to CD4(+) T lymphocytes (CD4TL). Directly involved in HIV-1 infection, DCIR is expressed in apoptotic or infected CD4TL and promotes trans-infection to bystander cells. Here we report the 3D modelling of the extracellular domain of DCIR. Based on this structure, two surface accessible pockets containing the carbohydrate recognition domain and the EPS binding motif, respectively, were targeted for screening of chemicals that will disrupt normal interaction with HIV-1 particle. Preliminary screening using Raji-CD4-DCIR cells allowed identification of two inhibitors that decreased HIV-1 attachment and propagation. The impact of these inhibitors on infection of DCs and CD4TL was evaluated as well. The results of this study thus identify novel molecules capable of blocking HIV-1 transmission by DCs and CD4TL.
authors.affiliation: Centre de recherche du CHU de Québec Infectious Diseases and Immunology, Quebec, Canada.
authors.forename: Alexandra A
authors.initials: AA
authors.lastname: Lambert
authors.forename: Arezki
authors.initials: A
authors.lastname: Azzi
authors.forename: Sheng-Xiang
authors.initials: SX
authors.lastname: Lin
authors.forename: Geneviève
authors.initials: G
authors.lastname: Allaire
authors.forename: Karianne P
authors.initials: KP
authors.lastname: St-Gelais
authors.forename: Michel J
authors.initials: MJ
authors.lastname: Tremblay
authors.forename: Caroline
authors.initials: C
authors.lastname: Gilbert
mesh_terms: D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D001665:Binding Sites; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D002460:Cell Line; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D055808:Drug Discovery; D015658:HIV Infections / Q000188:drug therapy / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D037181:Lectins, C-Type / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D011485:Protein Binding; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D016415:Sequence Alignment
chemical_list: D019380:Anti-HIV Agents; C423004:CLEC4A protein, human; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic