Suppression of CCR5-tropic HIV type 1 infection by OX40 stimulation via enhanced production of β-chemokines.
To elucidate the immunological role for the costimulatory molecule OX40 against the early stage of HIV-1 infection, fresh peripheral blood mononuclear cells (PBMCs) from normal donors were stimulated with immobilized anti-CD3 monoclonal antibody (mAb) together with soluble anti-CD28 mAb for 24 h, infected with CCR5-tropic (R5) HIV-1, and then cocultured in the presence or absence of OX40 ligand (OX40L). Results of these studied showed that OX40 stimulation led to a marked reduction in levels of p24, the frequency of intracellular p24(+) cells, as well as HIV-1-mediated syncytium formation. The suppression was reversed by anti-OX40L mAb. The mechanism underlying the R5 HIV-1 suppression was shown to be mediated in part by the CCR5-binding β-chemokines RANTES, MIP-1α, and MIP-1β, since the effect of the OX40 stimulation was reversed by a neutralizing antibody mixture against these three β-chemokines. Thus, OX40 stimulation enhanced the production of these CCR5-binding β-chemokines by the activated PBMCs and subsequently down-modulated CCR5 expression on the activated CD4(+) T cells. Taken together, the present data revealed a new role for OX40 in HIV-1 infection and documents the fact that OX40 stimulation suppresses the infection of primary activated PBMCs with R5 HIV-1 via enhanced production of R5 HIV-1 suppressing β-chemokines.
Tanaka
Reiko
R
Department of Immunology, Graduate School of Medicine, University of the Ryukyus, Nishihara-cho, Nakagami-gun, Okinawa, Japan. yuetsu@s4.dion.ne.jp
Takahashi
Yoshiaki
Y
Kodama
Akira
A
Saito
Mineki
M
Ansari
Aftab A
AA
Tanaka
Yuetsu
Y
D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D054405:Chemokine CCL3 / Q000378:metabolism; D054407:Chemokine CCL4 / Q000378:metabolism; D018946:Chemokine CCL5 / Q000378:metabolism; D019742:Chemokines, CC / Q000276:immunology*; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology*; D015497:HIV-1 / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D053278:OX40 Ligand / Q000276:immunology / Q000494:pharmacology*; D019713:Receptors, CCR5 / Q000276:immunology*; D053262:Receptors, OX40 / Q000276:immunology / Q000378:metabolism
D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D019742:Chemokines, CC; D053278:OX40 Ligand; D019713:Receptors, CCR5; D053262:Receptors, OX40