Two Orphan Seven-Transmembrane Segment Receptors Which Are Expressed in CD4-positive Cells Support Simian Immunodeficiency Virus Infection

Abstract

Clinical isolates of primate immunodeficiency viruses, including human immunodeficiency virus type 1 (HIV-1), enter target cells by sequential binding to CD4 and the chemokine receptor CCR5, a member of the seven-transmembrane receptor family. HIV-1 variants which use additional chemokine receptors are present in the central nervous system or emerge during the course of infection. Simian immunodeficiency viruses (SIV) have been shown to use CCR5 as a coreceptor, but no other receptors for these viruses have been identified. Here we show that two orphan seven-transmembrane segment receptors, gpr1 and gpr15, serve as coreceptors for SIV, and are expressed in human alveolar macrophages. The more efficient of these, gpr15, is also expressed in human CD4+ T lymphocytes and activated rhesus macaque peripheral blood mononuclear cells. The gpr15 and gpr1 proteins lack several hallmarks of chemokine receptors, but share with CCR5 an amino-terminal motif rich in tyrosine residues. These results underscore the potential diversity of seven-transmembrane segment receptors used as entry cofactors by primate immunodeficiency viruses, and may contribute to an understanding of viral variation and pathogenesis.

Apoptosis in SIV infection

“…HIV uses CXCR4 as an alternative coreceptor, whereas SIVs use several chemokine orphan receptors such as BOB/GPR15 and Bonzo/STRL33/CXCR6 for efficient infection and replication in vitro. [181][182][183] Several lines of evidence indicated that in vitro BOB/GPR15 is an important SIV coreceptor [184][185][186] exhibiting greater activity than CCR5. 184 Several reports have found that nonpathogenic SIV strains such as SIVagm, SIVsun, SIVlhoest, and SIVrcm use Bonzo/ STRL33/CXCR6 in vitro but less BOB/GPR15.…”

“…[181][182][183] Several lines of evidence indicated that in vitro BOB/GPR15 is an important SIV coreceptor [184][185][186] exhibiting greater activity than CCR5. 184 Several reports have found that nonpathogenic SIV strains such as SIVagm, SIVsun, SIVlhoest, and SIVrcm use Bonzo/ STRL33/CXCR6 in vitro but less BOB/GPR15. [187][188][189] In contrast, pathogenic SIV strains (SIVmne, SIVmac) have been reported to use in vitro both CCR5 and BOB/GPR15 but not Bonzo/STLR33/CXCR6.…”

“…[187][188][189] In contrast, pathogenic SIV strains (SIVmne, SIVmac) have been reported to use in vitro both CCR5 and BOB/GPR15 but not Bonzo/STLR33/CXCR6. [184][185][186] However, the in vivo role of BOB/GPR15 and Bonzo/STRL33/CXCR6 upon SIV infection is unknown and merit to be further explored.…”

Coreceptor usage of BOB/GPR15 and Bonzo/STRL33 by primary isolates of human immunodeficiency virus type 1.

“…In addition to CXCR4 and CCR5, several other members of the 7TM receptor family, namely CCR1, CCR2B, CCR3, CCR4, CCR8, CCR9, GPR15\ BOB, STRL33\Bonzo, GPR1, V28 and Apj, can be used by some HIV and SIV isolates Berger, 1997 ;Choe et al, 1996Choe et al, , 1998Doranz et al, 1996 ;Rucker et al, 1997 ;Owen et al, 1998 ;Liao et al, 1997 ;Deng et al, 1997 ;Farzan et al, 1997).…”

Orphan G-protein-coupled Receptors

“…The tissue expression pattern of GPRl was also examined by others (Farran et al , 1997). GPRl mRNA transcripts were detected in U87 cells and human alveolar macrophages, but not in primary human T lymphocytes, activated rhesus macque PBMCs, or CEMx174 (Farzan et at., 1997).…”