Aminooxypentane-RANTES, an Inhibitor of R5 Human Immunodeficiency Virus Type 1, Increases the Interferon gamma to Interleukin 10 Ratio without Impairing Cellular Proliferation

Abstract

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.

A Novel Substance Purified from Perilla Frutescens Britton Inhibits an Early Stage of HIV-1 Replication without Blocking Viral Adsorption

“…Since Pf-gp6 did not interfere with the binding of anti-CCR5 or anti-CXCR-4 mAb to the host cells, the substance is considered not to be a co-receptor antagonist. The inhibition of anti-chemokine receptor mAb binding has been reported on bicyclams (Schols et al, 1997), TAK-779 (Dragic et al, 2000), aminooxypentane-RANTES (Rusconi et al, 1999) and ALX40-4C (Doranz et al, 1997); however, they were found to be co-receptor antagonists. Another inhibitor similar to Pf-gp6 is a lipophosphoglycan from Leishmania (Martin et al, 1998).…”

α-Oxo Aldehyde or Glyoxylyl Group Chemistry in Peptide Bioconjugation

“…For example, chemokine RANTES features a Ser residue on the N-terminus. Periodate oxidation of RANTES followed by oxime bond formation with aminooxypentane generated aminooxypentane (AOP)-RANTES, a potent inhibitor of infection of diverse cell types by HIV-1. − This RANTES analogue was also produced by total chemical synthesis …”

“…Other medical areas have also benefited from glyoxylyl chemistry. A seminal contribution to the field is the design of chemokine RANTES analogues as anti-HIV agents. − …”

Cytokine and Chemokine Based Control of HIV Infection and Replication

“…Modified chemokines such as amino-oxypentane-RANTES (AOP-RANTES) and N-nonanoyl-RANTES (NNY-RANTES) efficiently bind to their own receptors and frequently show enhanced anti-HIV effects together with a decreased proinflammatory activity [50,[59][60][61]. Alternatively, RANTES has been used in combination with glycosaminoglycans, to reduce its proinflammatory activity [62] and still retaining the ability of inhibiting HIV replication [63]. A different approach could exploit the recent paradigm of viral decoy chemokines [64][65][66] and chemokine receptors [67], or engineering small peptides mimicking the N-terminus of CCR5 that have been shown to inhibit HIV in vitro [68].…”