Differential utilization of CCR5 by macrophage and T cell tropic simian immunodeficiency virus strains

Abstract

Certain chemokine receptors serve as cofactors for HIV type 1 envelope (env)-mediated cell-cell fusion and virus infection of CD4-positive cells. Macrophage tropic (M-tropic) HIV-1 isolates use CCR5, and T cell tropic (Ttropic) strains use CXCR4. To investigate the cofactors used by simian immunodeficiency viruses (SIV), we tested four T-tropic and two M-tropic SIV env proteins for their ability to mediate cell-cell fusion with cells expressing CD4 and either human or nonhuman primate chemokine receptors. Unlike HIV-1, both M-and T-tropic SIV envs used CCR5 but not CXCR4 or the other chemokine receptors tested. However, by testing a panel of CCR5͞CCR2b chimeras, we found that the structural requirements for CCR5 utilization by M-tropic and T-tropic SIV strains were different. T-tropic SIV strains required the second extracellular loop of CCR5 whereas a closely related M-tropic SIV strain could, like M-tropic HIV-1 strains, use the amino-terminal domain of CCR5. As few as two amino acid changes in the SIV env V3 domain affected the regions of CCR5 that were critical for fusogenic activity. Receptor signaling was not required for either fusion or infection. Our results suggest that viral tropism may be inf luenced not only by the coreceptors used by a given virus strain but also by how a given coreceptor is used.

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

“…These four Envs were also found to be just borderline or weakly positive for infection of human blood monocytes (Gao et al, 1996). As expected from previous studies (Chen et al, 1997 ;Edinger et al, 1997 ;Kirchhoff et al, 1997), the SIVmac239 Env mediated efficient entry into GHOST4 cells expressing CCR5, BOB\GPR15 or Bonzo\STRL33 (Fig. 1).…”

“…Both laboratory-adapted and primary HIV-2 isolates often use CXCR4 (Owen et al, 1998). Surprisingly, in contrast to HIV-1 and HIV-2, different SIV strains use CCR5 but not CXCR4 (Chen et al, 1997 ;Edinger et al, 1997 ;Kirchhoff et al, 1997 ;Marcon et al, 1997). It has been shown, however, that some additional members of the 7TM family, Bonzo\STRL33, BOB\GPR15 and GPR1, support efficient entry of different SIV strains with differential ability to replicate in macrophages Deng et al, 1997 ;Farzan et al, 1997 ;Liao et al, 1997).…”

High Beta-Chemokine Expression Levels in Lymphoid Tissues of Simian/Human Immunodeficiency Virus 89.6-Vaccinated Rhesus Macaques Are Associated with Uncontrolled Replication of Simian Immunodeficiency Virus Challenge Inoculum

“…However, recent studies have shown that high beta-chemokine levels correlate with the disease progression of SIV and HIV infections (25,27). It is worth noting that although SIVmac239 and SIVmac251 utilize CCR5 as their primary coreceptor, they can also use alternate coreceptors in vitro (8,15,17). Despite this ability to use alternate coreceptors in vitro, in vivo CCR5 seems to be the only coreceptor of consequence.…”

HIV-1 gp120 and chemokines activate ion channels in primary macrophages through CCR5 and CXCR4 stimulation

“…Macrophages are permissive for M-tropic R5 and dual-tropic R5X4 but not prototype T-tropic X4 strains, although some primary X4 isolates can use macrophage CXCR4 (11,12). Conversely, all primary simian immunodeficiency virus strains use CCR5 for entry (13)(14)(15), but determinants in Env regulate their ability to proceed through postentry steps of infection in macrophages (16). The basis for cell-and strainspecific differences in macrophage coreceptor function is not known.…”