CD26-processed RANTES(3-68), but not intact RANTES, has potent anti-HIV-1 activity.
The natural CC-chemokine RANTES(3-68), missing two NH2-terminal residues, has been isolated from leukocytes and tumor cells. The highly specific aminopeptidase dipeptidyl peptidase IV (DPP IV), also called CD26, was shown to be responsible for this NH2-terminal truncation of RANTES. Here it is reported that CD26/DPP IV treatment of RANTES enhances its anti-HIV-1 activity. RANTES(3-68) inhibited infection of PBMC by M-tropic HIV-1 strains ten-fold more efficiently than intact RANTES. This difference in antiviral potency between intact and truncated RANTES was even more pronounced (at least 25-fold) in CCR5-transfected cell lines. In HOS.CD4.CCR5 transfected cells, RANTES(1-68) had virtually no anti-HIV-1 activity (IC50 > 130 nM), whereas RANTES(3-68) was a potent inhibitor of HIV-1 replication (1C50: 5.5 nM). The anti-HIV-1 activity of RANTES(1-68) in the different cell types correlated with the expression of CD26. Moreover, the addition of soluble CD26 together with RANTES(1-68) significantly enhanced the antiviral activity of RANTES in HOS.CD4.CCR5 cells (IC50: 13 nM). These observations point to an important role of CD26-mediated processing of RANTES in inhibiting the replication of CCR5-binding HIV strains in HIV-infected persons and in preventing the development of AIDS.
Schols
D
D
Laboratory of Experimental Chemotherapy, Rega Institute for Medical Research, Leuven, Belgium. dominique.schols@rega.kuleuven.ac.be
Proost
P
P
Struyf
S
S
Wuyts
A
A
De Meester
I
I
Scharpé
S
S
Van Damme
J
J
De Clercq
E
E
D001667:Binding, Competitive; D002118:Calcium / Q000378:metabolism; D018946:Chemokine CCL5 / Q000737:chemistry / Q000378:metabolism*; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015658:HIV Infections / Q000276:immunology* / Q000378:metabolism; D015497:HIV-1; D006801:Humans; D019713:Receptors, CCR5 / Q000378:metabolism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D018946:Chemokine CCL5; D019713:Receptors, CCR5; D018819:Dipeptidyl Peptidase 4; D002118:Calcium