Aminooxypentane-RANTES, an inhibitor of R5 human immunodeficiency virus type 1, increases the interferon gamma to interleukin 10 ratio without impairing cellular proliferation.
Studies have demonstrated that the beta-chemokines RANTES, MIP-1alpha, and MIP-1beta suppress human immunodeficiency type 1 (HIV-1) replication in vitro. Infection with HIV-1 requires expression of CD4 antigen and the chemokine receptor CXCR4 (X4) or CCR5 (R5) on the surface of target cells. The engagement of these receptors with the viral surface proteins is essential for the membrane fusion process. This study investigated the anti-HIV-1 activity of a derivative of RANTES, the CCR5 antagonist aminooxypentane (AOP)-RANTES, on R5 HIV-1 isolates in peripheral blood mononuclear cells. In drug exposure experiments, AOP-RANTES efficiently inhibited viral replication of HIV-1 R5 strains, with a viral breakthrough observed after the withdrawal of the compound. The HIV-1-specific proliferative capacity was maintained under all conditions when compared with controls. An increase in IFN-gamma production accompanied by a parallel decrease in the generation of IL-10 was observed following the in vitro exposure of cells to AOP-RANTES in the presence of three of four HIV-1 R5 isolates. These experiments confirmed that the chemokine receptor antagonist AOP-RANTES was effective as an inhibitor of HIV-1 R5 strain infectivity in peripheral blood mononuclear cells. The capacity of this compound to maintain HIV-1-specific proliferative activity with a shift toward a type 1 cytokine profile makes this compound a unique molecule, one adopting an immunological pathway to limit HIV-1 infection.
Rusconi
S
S
Istituto di Malattie Infettive e Tropicali, Università di Milano, Ospedale Luigi Sacco, Milan, Italy. rusconi@imiucca.csi.unimi.it
La Seta-Catamancio
S
S
Kurtagic
S
S
Galazzi
M
M
Arienti
D
D
Trabattoni
D
D
Wilken
J
J
Thompson
D A
DA
Offord
R E
RE
Galli
M
M
Clerici
M
M
D019380:Anti-HIV Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D018946:Chemokine CCL5 / Q000031:analogs & derivatives* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis*; D016753:Interleukin-10 / Q000096:biosynthesis*; D013997:Time Factors
D019380:Anti-HIV Agents; D018946:Chemokine CCL5; C111989:aminooxypentane-RANTES; D016753:Interleukin-10; D007371:Interferon-gamma