Potent Inhibition of HIV-1 Infectivity in Macrophages and Lymphocytes by a Novel CCR5 Antagonist

TLDR

CXCR4 and CCR5 act as coreceptors with CD4 for HIV‑1 entry, yet chemokines such as RANTES only modestly inhibit infection in macrophages and could fail to suppress viral replication in non‑lymphocyte compartments while inducing inflammation. The study proposes that nanomolar CCR5 antagonists such as AOP‑RANTES could serve as effective therapies for HIV‑1 infection. AOP‑RANTES, a chemically modified RANTES lacking chemotactic activity, functions as a subnanomolar CCR5 antagonist in monocytes. AOP‑RANTES potently inhibited infection of macrophages and lymphocytes by macrophage‑tropic HIV‑1 strains, demonstrating that chemokine‑induced cell activation is unnecessary for viral inhibition.

Abstract

The chemokine receptors CXCR4 and CCR5 have recently been shown to act as coreceptors, in concert with CD4, for human immunodeficiency virus–type 1 (HIV-1) infection. RANTES and other chemokines that interact with CCR5 and block infection of peripheral blood mononuclear cell cultures inhibit infection of primary macrophages inefficiently at best. If used to treat HIV-1–infected individuals, these chemokines could fail to influence HIV replication in nonlymphocyte compartments while promoting unwanted inflammatory side effects. A derivative of RANTES that was created by chemical modification of the amino terminus, aminooxypentane (AOP)–RANTES, did not induce chemotaxis and was a subnanomolar antagonist of CCR5 function in monocytes. It potently inhibited infection of diverse cell types (including macrophages and lymphocytes) by nonsyncytium-inducing, macrophage-tropic HIV-1 strains. Thus, activation of cells by chemokines is not a prerequisite for the inhibition of viral uptake and replication. Chemokine receptor antagonists like AOP-RANTES that achieve full receptor occupancy at nanomolar concentrations are strong candidates for the therapy of HIV-1–infected individuals.