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CCR5 deficiency exacerbates T-cell-mediated hepatitis in mice - Clinical implications for CCR5 inhibition as antiretroviral therapy
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Hepatology
April 2006
Stefan Mauss 1, Massimo Puoti 2
1Center for HIV and Hepatogastroenterology, Duesseldorf, Germany
2University of Brescia, Italy
Potential conflict of interest: Nothing to report.
Letter to the editor
CCR5 Deficiency Exacerbates T-Cell-Mediated Hepatitis in Mice - Clinical Implications for CCR5 Inhibition as Antiretroviral Therapy
To the Editor:
In the paper authored by Christophe Moreno and colleagues, a more pronounced hepatotoxic reaction and an increased rate of liver associated mortality was observed in CCR5 deficient mice after exposure to Concanavalin A.[1] This observation is of particular interest as CCR5 inhibitors are currently studied as antiretroviral drugs for the treatment of HIV infection.[2][3] However, the development of aplaviroc was stopped recently due to hepatotoxic adverse events associated with jaundice observed in four study participants.[4] For maraviroc, another CCR5 inhibitor currently in phase III trials, at least one case of liver failure resulting in liver transplantation was observed (personal communication). However, details concerning this case were not disclosed by the manufacturer of the drug to the public.
The mechanism for the possible hepatotoxic reactions under treatment with CCR5 inhibitors remains unknown. In this context, the paper by Moreno and colleagues provides an intriguing hypothesis.[1] The results from the paper suggest an increased vulnerability to hepatotoxic agents due to CCR5 deficiency or pharmacological inhibition due to an imbalance in the cytokine response rather than a direct hepatotoxic action of the drug itself.
The impact of CCR5-delta32 mutation on the clinical course of hepatitis C is still controversial: increased susceptibility to chronic HCV infection, decreased necro-inflammatory activity and a reduced sensitivity to interferon monotherapy have all been reported in different populations.[5][6]
Given the relevant proportion of HIV-seropositive patients with hepatitis B or C coinfection in addition to other conditions of liver injury prevalent in the HIV-infected individuals (drugs, alcohol, steatosis) the potential of CCR5 blockade or deficiency to affect liver inflammation and progression of fibrosis deserves further attention.
In addition, the hypothetical vulnerability of patients with CCR5 deficiency due to the non-functional homozygous CCR5-delta32 allele may explain why individuals with this mutation represent only a small minority of the population <2% in most parts of the world.[7] Even in Northern Europe the prevalence is at most 10% of the population despite the partial protection against such deadly infections as the plague.[7]
References
1 Moreno C, Gusto T, Nicaise C, Quertinmot E, Nagy N, Parmentier M, et al. CCR5 deficiency exacerbates T-cell-mediated hepatitis in mice. HEPATOLOGY 2005; 42: 854-862. Links
2 Fatkenheuer G, Pozniak AL, Johnson MA, Plettenberg A, Staszewski S, Hoepelman A, et al. Efficacy of short-term monotherapy with maraviroc, a new CCR5 antagonist, in patients infected with HIV-1. Nat Med 2005; 11: 1170-1172. Links
3 Schuermann D, Pechardschek C, Rouzier R, Nougarede R, Faetkenheuer G, Ochlast I, et al. SCH 417690: antiviral activity of a potent new receptor antagonist. Third IAS Conference on HIV Pathogenesis and Treatment. Rio de Janeiro, July 24-27, 2005. Abstract TuOa0205.
4 Nichols WG, Steel HM, Bonny TM, Min SS, Curtis L, Kabeya K, et al. Hepatotoxicity observed in clinical trials of aplaviroc (APL 873140). Tenth European AIDS Conference. November 17-20 2005. Dublin. www.eacs-conference2005.com.
5 Hellier S, Frodsham AJ, Hennig BJ, Klenerman P, Knapp S, Ramaley P, et al. Association of genetic variants of the chemokine receptor CCR5 and its ligands, RANTES and MCP-2, with outcome of HCV infection. HEPATOLOGY 2003; 38: 1468-1476. Links
6 Ahlenstiel G, Woitas RP, Rockstroh J, Spengler U. CC-chemokine receptor 5 (CCR5) in hepatitis C - at the crossroads of the antiviral immune response? J Antimicrob Chemother 2004; 53: 895-898. Links
7 Galvani AP, Novembre J. The evolutionary history of the CCR5-Delta32 HIV-resistance mutation. Microbes Infect 2005; 7: 302-309. Links
Stefan Mauss 1, Massimo Puoti 2
1Center for HIV and Hepatogastroenterology, Duesseldorf, Germany
2University of Brescia, Italy
Reply:
Christophe Moreno, Jacques Deviere, Hubert Louis
Division of Gastroenterology and Hepato-Pancreatology, Erasme Hospital, Brussels, Belgium
Potential conflict of interest: Nothing to report.
Letter
Reply:
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-delta32 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-delta32 mutation, which would lead to a more pronounced inhibition of CCR5.
The impact of CCR5-delta32 mutation on the clinical course of chronic hepatitis C is still controversial, but the CCR5-32 mutation has already been linked to other liver diseases. First, the allele frequency of CCR5-32 is higher in patients with sclerosing cholangitis, and especially in patients suffering from severe liver disease.[5] Secondly, the CCR5-delta32 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-delta32 patients, it seems that CCR5 deficiency 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-delta32 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.
References
1 Dragic T, Litwin V, Allaway GP, Martin SR, Huang Y, Nagashima KA, et al. HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5. Nature 1996; 381: 667-673 Links
2 Samson M, Libert F, Doranz BJ, Rucker J, Liesnard C, Farber CM, et al. Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature 1996; 382: 722-725 Links
3 Moreno C, Gustot T, Nicaise C, Quertinmont E, Nagy N, Parmentier M, et al. CCR5 deficiency exacerbates T cell-mediated hepatitis in mice. HEPATOLOGY 2005; 42: 854-862 Links
4 Ajuebor M, Hogaboam C, Le T, Swain M. CCR5 deficiency unmasks a novel proinflammatory role for NK cells in murine experimental autoimmune hepatitis [Abstract 135]. HEPATOLOGY 2005; 42( Suppl 1): 250A. Links
5 Eri R, Jonsson JR, Pandeya N, Purdie DM, Clouston AD, Martin N, et al. CCR5-Delta32 mutation is strongly associated with primary sclerosing cholangitis. Genes Immun 2004; 5: 444-450. Links
6 Moench C, Uhrig A, Lohse AW, Otto G. CC chemokine receptor 5delta32 polymorphism-a risk factor for ischemic-type biliary lesions following orthotopic liver transplantation. Liver Transpl 2004; 10: 434-439. Links
7 Dawson TC, Beck MA, Kuziel WA, Henderson F, Maeda N. Contrasting effects of CCR5 and CCR2 deficiency in the pulmonary inflammatory response to influenza A virus. Am J Pathol 2000; 156: 1951-1959. Links
8 Welniak LA, Wang Z, Sun K, Kuziel W, Anver MR, Blazar BR, et al. An absence of CCR5 on donor cells results in acceleration of acute graft-vs-host disease. Exp Hematol 2004; 32: 318-324. Links
9 Moreno C, Nicaise C, Gustot T, Quertinmont E, Nagy N, Louis H, et al. Lack of the Chemokine Receptor CCR5 exacerbates acute pancreatitis in mice. Acta Gastro-Enterologica Belgica 2006; 69: D48. Links
Christophe Moreno, Jacques Deviere, Hubert Louis
Division of Gastroenterology and Hepato-Pancreatology, Erasme Hospital, Brussels, Belgium
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