Association of genetic variants of the chemokine receptor CCR5 and its ligands, RANTES and MCP-2, with outcome of HCV infection

Abstract

The effect of host genetic variation on the outcome of hepatitis C virus (HCV) infection and its treatment is poorly understood. The chemokine receptors CCR5, CCR2, and CCR3 and their ligands, RANTES, MCP-1, MCP-2, and MIP-1␣, are involved in the immune responses and the selective recruitment of lymphocytes to the liver in HCV infection. We studied 20 polymorphisms within these genes and investigated their association with persistent carriage of HCV, severity of liver disease, hepatic inflammation, and response to treatment in a large European cohort. Significant associations were found between CCR5-⌬32 and reduced portal inflammation (P ‫؍‬ H epatitis C virus (HCV) is a major global health problem with 1% to 2% of the world's population chronically infected. The prevalence of infection in the United Kingdom is approximately 0.5%, 1 but it is likely that this figure will continue to rise as more cases come to light. Persistent HCV infection has a very variable outcome, with 25% of those infected developing cirrhosis within 20 years, of whom 3% to 5% per year will proceed to hepatocellular carcinoma. A further 5% per year will develop liver failure, and 2% per year will die of a liver-related death. There is also a very variable response to treatment because only 40% of those treated with interferon alfa and ribavirin successfully clear the virus. 2,3 There are a number of epidemiologic and viral factors that influence susceptibility to persistent HCV infection, progression of HCV-related liver disease, and response to treatment, but host genetic factors are also influential. This study has examined 20 polymorphisms in the genes for the CC chemokine receptors (CCR) CCR5, CCR2, and CCR3 and their ligands, RANTES (regulated and normal T-cell expressed and secreted), MCP-1 (monocyte chemotactic protein), MCP-2, and MIP-1␣ (macrophage inflammatory protein), to try and elucidate their role in the immunopathologic outcome of HCV infection..Chemokines constitute a large family of small (8-10 kD) cytokines that are up-regulated in inflammation and whose effects are mediated by members of a family of 7 transmembrane domain, G protein-coupled receptors. 4 Their major role is in leukocyte migration and dependent processes such as immune surveillance and innate and adaptive immune responses. Chemokines have been

A novel I-TAC promoter polymorphic variant is functional in the presence of replicating HCV in vitro

“…For example, several CC chemokine polymorphisms have been associated with susceptibility to HCV and disease progression, including the gene for RANTES and its receptor CCR5, and MCP-1 (Woitas et al, 2002;Hellier et al, 2003;Muhlbauer et al, 2003). Hellier et al (2003) identified a polymorphism at position -403 in the RANTES gene promoter and in the CCR5 32 allele that was associated with reduced hepatic portal inflammation. Furthermore, the −403 RANTES polymorphism appears to be functional with the −403A allele leading to increased transcription of RANTES.…”

“…The majority of T cells within the HCV infected liver are known to preferentially express the chemokine receptors CCR5 and CXCR3 (Shields et al, 1999 andHarvey et al, 2003), suggesting that the CC and CXC chemokines play an important role in the inflammatory process of the HCV infected liver. Several CC chemokine polymorphisms have been associated with susceptibility to HCV and disease progression, including the CCR5 32, RANTES −403A and MCP-1 −2518G polymorphic variants (Woitas et al, 2002;Hellier et al, 2003;Muhlbauer et al, 2003). However, to our knowledge no polymorphic variants in the CXCR3 family of chemokines have been identified to play a functional role in chronic HCV.…”

Role of chemokines polymorphisms in diseases

“…and CCR3 [25] and reported four main findings: (i) the CCR5 32 allele is associated with mild fibrosis and reduced portal inflammation; (ii) polymorphisms in a CCR5 promoter-the 2132-C allele-are associated with increased risk of HCV persistence and with better initial response to interferon; (iii) the CCL5-403 promoter polymorphism is associated with portal inflammation; and (iv) the MCP-2 Q46K mutation is associated with more severe fibrosis. The British study by Goulding et al [26] confirmed the protective role of the CCR5 32 allele in HCV, but a Spanish study [27] reached the opposite conclusion, finding the frequency of the CCR5 32 allele did not differ between case and control groups.…”

Adaptive Gene Loss? Tracing Back the Pseudogenization of the Rabbit CCL8 Chemokine

“…In contrast, in naïve European rabbit, this large DNA virus causes a systemic immune deficiency with a fatal outcome (reviewed in Abrantes et al 2012;Spiesschaert et al 2011). Numerous studies have documented the crucial role played by CCL8 and its posttranslational byproducts in CCR5-dependent signal transduction (Hellier et al 2003;Loetscher et al 1994;Struyf et al 2009), more in particular in Human during infection by HIV (Moser et al 2004;Proost et al 1998a, b).…”