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.

Virus Entry via the Alternative Coreceptors CCR3 and FPRL1 Differs by Human Immunodeficiency Virus Type 1 Subtype

“…1B). We also did not have access to NP-2/CD4 target cells expressing GPR15 or D6, two alternative CoRs previously reported to mediate infection of other target cell lines (22,55). It is possible that examination of these two additional alternative CoRs could add to the differences between HIV-1 subtypes that we observed.…”

“…CXCR4 is an additional CoR for up to 50% of subtype B and D HIV-1 isolates at very late stages of disease (4,7,28,35). Many other seven-membrane-spanning G-protein-coupled receptors (GPCRs) have been identified as alternative CoRs when expressed on various target cell lines in vitro, including CCR1 (76,79), CCR2b (24), CCR3 (3,5,17,32,60), CCR8 (18,34,38), GPR1 (27,65), GPR15/BOB (22), CXCR5 (39), CXCR6/Bonzo/STRL33/TYMSTR (9,22,25,45,46), APJ (26), CMKLR1/ChemR23 (49,62), FPLR1 (67,68), RDC1 (66), and D6 (55). HIV-2 and simian immunodeficiency virus SIVmac isolates more frequently show expanded use of these alternative CoRs than HIV-1 isolates (12,30,51,74), and evidence that alternative CoRs other than CXCR4 mediate infection of primary target cells by HIV-1 isolates is sparse (18,30,53,81).…”

Induction of Glial Fibrillary Acidic Protein Expression in Astrocytes by Nitric Oxide

“…Involvement of NO in proinflammatory cytokine-, dsRNA-, A␤1-42-, and HIV-1 gp120-mediated increase in GFAP expression in mouse primary astrocytes Astrocytes are activated under various pathological conditions, such as inflammation and viral infection (Wang et al, 1993;Eng et al, 1994;Suryadevara et al, 2003;Neil et al, 2005). Because LPS increased the expression of GFAP in astrocytes via NO, we investigated whether other inducers of NO production also increased the expression of GFAP via NO.…”

Gamma Interferon Primes Productive Human Immunodeficiency Virus Infection in Astrocytes

“…This may be a consequence of the laboratory-adapted HIV IIIB strain; therefore, primary T-tropic or dualtropic strains may still be responsive to IFN-␥ pretreatment of astrocytes. Recently, the CC chemokine coreceptor D6 was identified as a functional coreceptor for dualtropic HIV infection of astrocytes (19). These studies indicate that pretreatment of astrocytes with cytokines can prime them for HIV infection, resulting in substantial virus production in astrocytes.…”