HIV co-receptors as targets for antiviral therapy.

Abstract

The chemokine receptors CXCR4 and CCR5 are used as the main co-receptors by the T-cell-tropic (CXCR4-dependent, X4) and macrophage-tropic (CCR5-dependent, R5) HIV-1 strains, respectively, for entering their target cells. The natural ligands for CXCR4, the CXC-chemokine SDF-1 and CCR5, the CC-chemokines RANTES, MIP-1alpha and MIP-1beta are described to inhibit viral entry. In this review we focus on chemokine receptor/HIV co-receptor inhibitors. Modified chemokines such as Met-RANTES and AOP-RANTES showed antiviral activity against R5 viruses. Several low-molecular weight CCR5 antagonists have been described (such as TAK-779 and SCH-C) with potent antiviral activity. The latter compound is also orally available and is able to decrease R5 viral load levels in HIV-infected subjects. Several peptidic compounds, such as T22 (an 18-mer), T134 (a 14-mer), ALX40-4C (a 9-mer) and CGP 64222 (also a 9-mer) have anti-HIV activity and have been identified as CXCR4 antagonists. Also, the HIV-1 Tat protein has been described as a "natural" CXCR4 antagonist with anti-HIV-1 activity. The most potent and specific CXCR4 antagonists are the bicyclam derivatives, which also potently inhibit X4 HIV replication. AMD3100 has proved to be a highly specific CXCR4 antagonist, which consistently blocks X4 viral replication in any target cell-type evaluated so far. AMD3100 was selected as the clinical drug candidate, which, after initial phase I (safety) studies, had proceeded to phase II (efficacy) trials. The compound dose-dependently inhibited X4 viruses after 10 days of continuous infusion of the drug. Recently, the orally bioavailable CXCR4 antagonist, AMD070, is presented as a candidate HIV drug. We believe that chemokine receptor antagonists will become important new antiviral drugs to combat AIDS. Both (CXCR4 and CCR5) chemokine receptor inhibitors will be needed in combination to inhibit viral replication and even in combinations of antiviral drugs that also target other aspects of the HIV replication cycle, such as reverse transcriptase and protease, to obtain optimum therapeutic effects.