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Ten years ago, the chemokine receptor CCR5 was shown to act as a cofactor for entry of macrophage-tropic strains of HIV-1.1 Individuals homozygous with the CCR5-Δ32 mutation, a 32-bp deletion in the CCR5 gene resulting in a non-functional protein, are protected against HIV-1 infection. These heterozygotes also disclose a delayed progression to AIDS.2 CCR5 inhibitors present themselves as promising new drugs. Currently studied for the treatment of HIV infection, they have recently been associated with the development of severe hepatotoxicity.

In our study,3 CCR5-deficient mice disclosed increased mortality and liver injury in a model of T cell-mediated liver injury. As pointed by Mauss and Puoti, this was apparently not due to a direct hepatotoxic action of Concanavalin A. CCR5-deficient mice exhibited increased production of CC chemokines leading to a more prominent liver mononuclear cell infiltrate, in particular CCR1+ cells. The increased production of chemokines played a crucial role in worsening liver injury since their simultaneous in vivo neutralization dramatically reduced the severity of hepatitis in CCR5-deficient mice. Recently, another group confirmed that CCR5 deficiency increased the severity of T cell–mediated liver disease and suggested that liver infiltration by NK cells was also involved in the increased liver susceptibility to Concanavalin A in CCR5-deficient mice.4

Along the same lines, it would be interesting to know if patients who developed severe hepatic adverse events due to CCR5 inhibitors disclosed high CC chemokines plasma levels and a pronounced liver inflammatory infiltration by T cells. It would also be interesting to know if these patients are heterozygotes of the CCR5-Δ32 mutation, which would lead to a more pronounced inhibition of CCR5.

The impact of CCR5-Δ32 mutation on the clinical course of chronic hepatitis C is still controversial, but the CCR5-Δ32 mutation has already been linked to other liver diseases. First, the allele frequency of CCR5-Δ32 is higher in patients with sclerosing cholangitis, and especially in patients suffering from severe liver disease.5 Secondly, the CCR5-Δ32 mutation has been reported as a risk factor in the development of ischemic-type biliary lesions after liver transplantation and increased mortality.6

In addition to the hypothetical liver vulnerability of homozygous CCR5-Δ32 patients, it seems that CCR5 de

ficiency may increase the susceptibility to other diseases.7, 8 Preliminary results from our laboratory also suggest that CCR5-deficient mice disclose higher susceptibility to experimental pancreatitis.9 This may explain why CCR5-Δ32 mutation represents only a small minority of the population in most parts of the world.

The recent observation of a hepatotoxic adverse event in patients treated with CCR5 inhibitors is consistent with our experimental observations. As pointed by S. Mauss and M. Puoti, HIV patients are frequently exposed to other hepatotoxic agents (virus, alcohol, drugs). The hypothetical vulnerability of patients with CCR5 deficiency must be kept in mind for the future use of CCR5 inhibitors.

Christophe Moreno*, Jacques Devière*, Hubert Louis*, * Division of Gastroenterology and Hepato-Pancreatology, Erasme Hospital, Brussels, Belgium.

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