Interpreting and Understanding:
"CC CKR5: A RANTES, MIP-1a, MIP-1B Receptor as a Fusion Cofactor
for Macrophage-Tropic HIV-1"
- HIV virus type 1 (HIV-1) uses fusin as a cofactor, with
CD4+cells in order to enter the cell.
- Fusin is a coupled coreceptor, G protein. It is a cofactor for T-tropic strains of the HIV virus.
- Certain chemokines inhibit cell fusion by inhibiting infection by M-tropic cell lines. This is done selectively through mediation by
analogous envelope glycoproteins. These specific chemokines are RANTES, MIP-1a, AND MIP-1B.
- CC CKR5 is a recombinant coupled receptor, G protein for the aforementioned chemokines. CC CKR5 conferred CD4-expressing,
nonhuman cells able to employ fusin preferentially with M-tropic envelope glycoproteins.
- CC CKR5 mRNA was selectively found in cells likely to be infected by M-tropic lines.
- This leads to the conclusion that CC CKR5 is a cofactor for M-tropic HIV-1 strains.
Questions/Purpose of Study
- To study the specific cytotropisms for infection of primary macrophages on HIV-1 isolates versus infectection on CD4+ T cell isolates.
This cytotropism is determined by the corresponding envelope glycoprotein, where HIV binds. It is suggested that the cytotropism of the
various isolates is a result of the inherent membrane fusion selectivities of the analogous envelope glycoproteins for different CD4+ target
- Suppressive C-C chemokines exert infection-inhibition by binding to a chemokine receptor that acts as a fusion cofactor for M-tropic
HIV-1 isolates, thus inhibiting fusion determined by the corresonding envelope glycoprotein.
Methods of Study
- Direct assays (vaccina-based) of fusion mediated recombinant envelope glycoproteins.
- Recombinant vaccina-based systems where fusion between envelope-expressing (Envs-expressing) and CD4-expressing cells
causes expression of E. coli lacZ gene. Thus, B-galactosidase (B-gal) is produced in fused cells, selectively.
- Measurement of cell specificity with these assays
- Examination of effects of C-C chemokines on fusion reaction, using phytohemagglutinin PHA-activated peripheral blood
mononuclear cells (PBMC's). ---used as the CD4+ target cell type.
- Comparison of envelope glycoproteins from prototypic M-tropic Ba-L isolate and T-tropic LAV isolate.
- Tested effects of C-C chemokines on fusion by CC CKR5 and CD4
- DNA probing
- Northern blot analysis
- Recombinant CC CKR5 allowed nonhuman cells to go through fusion, mediated by Envs from M-tropic isolates.
- Inhibition of Ba-L Env-mediated fusion according to dose, in RANTES, MIP-1a, MIP1B, not in MCP-1, MCP-3
- The presence of a correspondence between CC CKR5 selectivity and specificity of chemokine inhibition of HIV infection and Env/CD4
determined cell fusion with human PBMCs and nonhuman cells coexpressing CC CKR5 and CD4.
- Differences in expression levels of different target cell molecules affects inhibition quantitatively.
- CC CKR5 and fusin are the only fusion cofactors for HIV-1 (One must also take into account the corresponding Envs.)
- Practical applications in transgenic models of HIV-1 infection
- Possible treatment of HIV-1 infection
- Chemokines RANTES, MIP-1a, MIP-1B may have possible theraputic effects, as they are now known to have suppressive activity.
The University of Arizona
Biology 181 Honors
Last Updated: December 5, 2002
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