The Promiscuous CC Chemokine Receptor D6 Is a Functional Coreceptor for Primary Isolates of Human Immunodeficiency Virus Type 1 (HIV-1) and HIV-2 on Astrocytes

ABSTRACT The role of coreceptors other than CCR5 and CXCR4 in the pathogenesis of human immunodeficiency virus (HIV) disease is controversial. Here we show that a promiscuous CC chemokine receptor, D6, can function as a coreceptor for various primary dual-tropic isolates of HIV type 1 (HIV-1) and HIV-2. Furthermore, D6 usage is common among chimeric HIV-1 constructs bearing the gp120 proteins of isolates from early seroconverting patients. D6 mRNA and immunoreactivity were demonstrated to be expressed in HIV-1 target cells such as macrophages, peripheral blood mononuclear cells, and primary astrocytes. In primary astrocytes, an RNA interference-mediated knockdown of D6 expression inhibited D6-tropic isolate infection. D6 usage may account for some previous observations of alternative receptor tropism for primary human cells. Thus, D6 may be an important receptor for HIV pathogenesis in the brain and for the early dissemination of virus in the host.

[1]  J. Hoxie,et al.  Trophoblasts are productively infected by CD4-independent isolate of HIV type 1. , 2002, AIDS research and human retroviruses.

[2]  R. Nibbs,et al.  The chemokine receptor D6 constitutively traffics to and from the cell surface to internalize and degrade chemokines. , 2004, Molecular biology of the cell.

[3]  J. Esko,et al.  Contribution of Proteoglycans to Human Immunodeficiency Virus Type 1 Brain Invasion , 2004, Journal of Virology.

[4]  E. De Clercq,et al.  CXCR4 as a Functional Coreceptor for Human Immunodeficiency Virus Type 1 Infection of Primary Macrophages , 1998, Journal of Virology.

[5]  H. Whittle,et al.  A Broad Range of Chemokine Receptors Are Used by Primary Isolates of Human Immunodeficiency Virus Type 2 as Coreceptors with CD4 , 1998, Journal of Virology.

[6]  D. Gabuzda,et al.  Chemokine receptors in HIV-1 infection of the central nervous system. , 1998, Seminars in immunology.

[7]  J. Sodroski,et al.  CCR3 and CCR5 are co-receptors for HIV-1 infection of microglia , 1997, Nature.

[8]  R. Nibbs,et al.  Chemokines on the move: control by the chemokine "interceptors" Duffy blood group antigen and D6. , 2003, Seminars in immunology.

[9]  R. Doms,et al.  Placental expression of DC‐SIGN may mediate intrauterine vertical transmission of HIV , 2001, The Journal of pathology.

[10]  Y. Matsuo,et al.  Differential gene‐expression profiling in the leukemia cell lines derived from indolent and aggressive phases of CD56+ T‐cell large granular lymphocyte leukemia , 2004, International journal of cancer.

[11]  John P. Moore,et al.  The CCR5 and CXCR4 coreceptors--central to understanding the transmission and pathogenesis of human immunodeficiency virus type 1 infection. , 2004, AIDS research and human retroviruses.

[12]  M. Tremblay,et al.  Endocytic Host Cell Machinery Plays a Dominant Role in Intracellular Trafficking of Incoming Human Immunodeficiency Virus Type 1 in Human Placental Trophoblasts , 2004, Journal of Virology.

[13]  David Cornforth,et al.  Development of the antibody response in acute HIV-1 infection , 2004, AIDS.

[14]  C. Broder,et al.  CC CKR5: a RANTES, MIP-1alpha, MIP-1beta receptor as a fusion cofactor for macrophage-tropic HIV-1. , 1996, Science.

[15]  J. Kónya,et al.  Induction of HIV-1 replication in latently infected syncytiotrophoblast cells by contact with placental macrophages: role of interleukin-6 and tumor necrosis factor-alpha. , 2001, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[16]  A. Kingsman,et al.  A transient three-plasmid expression system for the production of high titer retroviral vectors. , 1995, Nucleic acids research.

[17]  B. Navia,et al.  Neuropathology of Acquired Immunodeficiency Syndrome (AIDS): An Autopsy Review , 1986, Journal of neuropathology and experimental neurology.

[18]  R. Nibbs,et al.  Cloning and characterization of a novel murine beta chemokine receptor, D6. Comparison to three other related macrophage inflammatory protein-1alpha receptors, CCR-1, CCR-3, and CCR-5. , 1997, The Journal of biological chemistry.

[19]  Virginia Litwin,et al.  HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5 , 1996, Nature.

[20]  Á. McKnight,et al.  Cell surface receptors, virus entry and tropism of primate lentiviruses. , 2002, The Journal of general virology.

[21]  C. Wiley,et al.  Human Immunodeficiency Virus Infection of the Brain: Pitfalls in Evaluating Infected/Affected Cell Populations , 2004, Brain pathology.

[22]  Alberto Mantovani,et al.  β-Arrestin-dependent Constitutive Internalization of the Human Chemokine Decoy Receptor D6* , 2004, Journal of Biological Chemistry.

[23]  A. Nath,et al.  CD4-Independent Infection of Astrocytes by Human Immunodeficiency Virus Type 1: Requirement for the Human Mannose Receptor , 2004, Journal of Virology.

[24]  D. Kerjaschki,et al.  The beta-chemokine receptor D6 is expressed by lymphatic endothelium and a subset of vascular tumors. , 2001, The American journal of pathology.

[25]  S. Henderson,et al.  Kaposi sarcoma herpesvirus–induced cellular reprogramming contributes to the lymphatic endothelial gene expression in Kaposi sarcoma , 2004, Nature Genetics.

[26]  R. Weiss,et al.  Primary, syncytium-inducing human immunodeficiency virus type 1 isolates are dual-tropic and most can use either Lestr or CCR5 as coreceptors for virus entry , 1996, Journal of virology.

[27]  R. Nibbs,et al.  Cloning and Characterization of a Novel Promiscuous Human β-Chemokine Receptor D6* , 1997, The Journal of Biological Chemistry.

[28]  Stephen J O'Brien,et al.  Human genes that limit AIDS , 2004, Nature Genetics.

[29]  J. Bell,et al.  Identification of a Subset of Human Immunodeficiency Virus Type 1 (HIV-1), HIV-2, and Simian Immunodeficiency Virus Strains Able To Exploit an Alternative Coreceptor on Untransformed Human Brain and Lymphoid Cells , 2003, Journal of Virology.

[30]  G. Vassart,et al.  Mapping of the CCXCR1, CX3CR1, CCBP2 and CCR9 genes to the CCR cluster within the 3p21.3 region of the human genome , 2000, Cytogenetic and Genome Research.

[31]  C. Broder,et al.  CC CKR5: A RANTES, MIP-1α, MIP-1ॆ Receptor as a Fusion Cofactor for Macrophage-Tropic HIV-1 , 1996, Science.

[32]  M. Gobbi,et al.  Cutting Edge: Scavenging of Inflammatory CC Chemokines by the Promiscuous Putatively Silent Chemokine Receptor D6 1 , 2003, The Journal of Immunology.

[33]  G. Simmons,et al.  Primary Human Immunodeficiency Virus Type 2 (HIV-2) Isolates Infect CD4-Negative Cells via CCR5 and CXCR4: Comparison with HIV-1 and Simian Immunodeficiency Virus and Relevance to Cell Tropism In Vivo , 1999, Journal of Virology.

[34]  M. Auer,et al.  Transcytosis and Surface Presentation of IL-8 by Venular Endothelial Cells , 1997, Cell.

[35]  Y. Soda,et al.  Establishment of a new system for determination of coreceptor usages of HIV based on the human glioma NP-2 cell line. , 1999, Biochemical and biophysical research communications.