Inhibition of HIV-1 infection by a CCR5-binding cyclophilin from Toxoplasma gondii.
The activation of murine dendritic cells by Toxoplasma gondii has recently been shown to depend on a parasite protein that signals through the chemokine receptor CCR5. Here we demonstrate that this molecule, cyclophilin-18 (C-18), is an inhibitor of HIV-1 cell fusion and infection with cell-free virus. T gondii C-18 efficiently blocked syncytium formation between human T cells and effector cells expressing R5 but not X4 envelopes. Neither human nor Plasmodium falciparum cyclophilins possess such inhibitory activity. Importantly, C-18 protected peripheral blood leukocytes from infection with multiple HIV-1 R5 primary isolates from several clades. C-18 bound directly to human CCR5, and this interaction was partially competed by the beta-chemokine macrophage inflammatory protein 1 beta (MIP-1 beta) and by HIV-1 R5 gp120. In contrast to several other antagonists of HIV coreceptor function, C-18 mediated inhibition did not induce beta-chemokines or cause CCR5 downmodulation, suggesting direct blocking of envelope binding to the receptor. These data support the further development of C-18 derivatives as HIV-1 inhibitors for preventing HIV-1 transmission and for postexposure prophylaxis.
Golding
Hana
H
Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Bldg 29A, Rm 1A21, 8800 Rockville Pike, Bethesda, MD, 20892, USA. goldingh@cber.fda.gov
Aliberti
Julio
J
King
Lisa R
LR
Manischewitz
Jody
J
Andersen
John
J
Valenzuela
Jesus
J
Landau
Nathaniel R
NR
Sher
Alan
A
D000818:Animals; D019380:Anti-HIV Agents / Q000378:metabolism / Q000494:pharmacology; D001667:Binding, Competitive; D021983:Cyclophilins / Q000378:metabolism / Q000494:pharmacology*; D015726:Giant Cells / Q000187:drug effects; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D015658:HIV Infections / Q000517:prevention & control*; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000821:virology; D011485:Protein Binding / Q000187:drug effects; D015800:Protozoan Proteins / Q000378:metabolism / Q000494:pharmacology; D019713:Receptors, CCR5 / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology / Q000821:virology; D014122:Toxoplasma / Q000737:chemistry*
D019380:Anti-HIV Agents; D015699:HIV Envelope Protein gp120; D015800:Protozoan Proteins; D019713:Receptors, CCR5; D021983:Cyclophilins