furthermore , these molecules are involved in modulation of adhesion processes at the endothelium and thus promote the transendothelial migration of leukocytes ( haptotaxis ) . in addition , some chemokines stimulate angiogenesis or angiostasis and thus may play a further role in the suppression of tumor growth or the establishment of an inflammatory response . traditionally , chemokines and chemokine receptors have been classified into four families ( cxc , cc , c and cx3c ) . several years ago , a new nomenclature was introduced in which each ligand and each receptor is identified as a member of a sub - family and carries a special number . for example , a chemokine designated ccl5 is a member of the cc sub - family with the number 5 . this special chemokine was formerly known as rantes . despite their essential importance for the immune system chemokines and chemokine receptors these include autoimmune diseases , cancer , lung , and vascular diseases   as well as transplant rejection [ 7 - 10 ] . in addition , the human immunodeficiency virus ( hiv ) uses different chemokine receptors as co - receptors for entry into the cell . they activate specific inflammatory cells such as monocytes or t lymphocytes and recruit them to the site of inflammation . these cc chemokines bind to specific g protein - coupled receptors , thereby initiating activation and migration of cells . the cc chemokines ccl3 ( mip-1 ) , ccl4 ( mip-1 ) , ccl5 ( rantes ) , and ccl3l1 are the natural ligands of the cc - chemokine receptor ccr5 ( ccckr5 , chemr13 or cmkbr5 ) . the coding sequence for this receptor is located at position 21 on the short arm of chromosome 3 and has a coding sequence of 1056 base pairs , which is translated into a protein of 352 amino acid length . based on their cytokine profile cd4-positive t - cells can be divided into different subclasses : th1 cells ( t helper cells type 1 ) secrete il-2 , ifn- and lymphotoxin , whereas th2 cells produce il-4 , il-5 , il-6 , il-9 , il-10 , and il-13 . th1 cells primarily control the cellular immune response and appear to be involved in chronic inflammatory processes . th2 cells support the formation of specific antibodies by increasing the b - cell proliferation and their differentiation into plasma cells and play an important role in the development of allergic reactions due to the promotion of ige production . interestingly , the expression of specific chemokine receptors is closely associated with the differentiation and activation of specific inflammatory cells . thus , the ccr5 receptor is expressed on th1 lymphocytes   but not on th2 lymphocytes , which primarily express ccr3 , and ccr8 and ccr4 . beyond th1 cells , ccr5 has also been detected on monocytes , memory t cells ( cd45ro ) , stem cells , dendritic cells , microglia , and on a main group of cytotoxic cd8 ( + ) t lymphocytes . infiltration of mononuclear inflammatory cells is a central feature of hepatitis c virus ( hcv ) infection . here , many of the liver - infiltrating cells express high levels of the ccr5 receptor . moreover , high levels of the chemokines ccl3 , ccl4 and ccl5 can be found in the hcv - infected liver . in vitro data for instance , it could be shown that binding of the hcv e2 envelope protein to the tetraspanin cd81 , which serves as a co - receptor for hcv , induces release of the ccr5 ligand ccl5 by cd8 ( + ) t cells . in addition , the hcv core and ns5a proteins have been demonstrated to affect ccl5 secretion by modulating ccl5 promoter activity . of note , ccr5 has been shown to promote hepatic fibrosis in mice and marked up - regulation of ccl5 and ccr5 has been found in patients with hepatic cirrhosis , confirming activation of the cc chemokine system in human fibrogenesis . in contrast to the infected liver significantly reduced numbers of ccr5-expressing lymphocytes can be found in the peripheral blood of hcv - infected patients . this may be due to hcv - induced intrahepatic chemokine secretion mediating the hepatic recruitment of ccr5-mediated hepatic ( + ) t - cell and thus reflect altered compartmentalization of ccr5(+ ) lymphocytes . a strong anti - viral type 1 immune response has been shown to be associated with a successful elimination of the virus , both during the acute phase of infection and an antiviral therapy [ 18 - 20 ] . this would suggest that accumulation of ccr5 ( + ) th1 cells in the hcv - infected liver contributes to an effective antiviral immune response . however , these relationships appear to be more complex . we recently showed that ccr5 ( + ) lymphocytes are characterized by a high expression of the inhibitory nk cell receptor nkg2a . therefore , these cells are very sensitive to nkg2a - mediated inhibition of cytotoxic function . as hepatitis c is associated with a high intrahepatic expression of the nkg2a ligand hla - e , intra - hepatic accumulation of ccr5(+)nkg2a(+ ) lymphocytes could interfere with an effective immune response . in addition , ccr5 ( + ) t cells may have a role in immune - mediated liver cell damage during chronic hepatitis c . the ccr5 gene is subject to various mutations , including a deletion of 32 base pairs . this mutation , called ccr532 , leads to a shift in the reading frame , resulting in the formation of a truncated , non - functional protein , which is not expressed on the cell surface . in a caucasian population thus , it is believed that this mutation first occurred in northern europe not so long ago . individuals who are homozygous for the mutation and thus " genetically negative " for ccr5 , develop normal and are healthy . therefore , it was originally presumed that the ccr5 receptor has no relevant importance to the immune system . in further studies , however , it could be shown that lack of ccr5 is associated with a significantly altered immune response in mice . for example , infection with cryptpcoccus neoformans is often fatal in ccr5-deficient mice , whereas wild - type mice survive . furthermore , experiments using ccr5 knockout demonstrated that lack of ccr5 is associated with an increased t - cell immune response in various infectious diseases [ 25 - 27 ] . even in non - infectious inflammatory reactions ccr5 recently , it has been reported that ccr5-deficient mice , in which a t cell - mediated autoimmune hepatitis had been induced , displayed a significantly greater liver damage in comparison to ccr5-positive mice . studies on the clinical relevance of ccr532 mutation in humans indicated that absence of the ccr5 receptor may , under certain circumstances , have either a positive or a negative effect . patients carrying a homozygous ccr532-genotype have a higher risk of death during infection with west nile virus . on the other hand , it is presumed that the absence of ccr5 confers some protection against infection with smallpox ( or the plague ) , which is reflected by the relatively high prevalence of this mutation in central and northern europe . moreover , ccr5 has been suggested to play a role in transplant rejection [ 7 - 10,30 ] . for instance , a prospective , biopsy - controlled study suggested that the local expression of the ccr5-ligand rantes ( ccl5 ) leads to the directional movement of activated ccr5 bearing t cells into the renal allograft thereby mediating acute rejection . reported patients homozygous for ccr532 to show longer survival of renal transplants than those with other genotypes . in contrast , bickerstaff and coworkers found rapid rejection of renal allografts in ccr5-/- mice with many histopathologic features observed during ahr of human renal allografts . with respect to hcv infection data regarding the importance of ccr532 mutation are conflicting . woitas et al . reported that patients with chronic hcv infection were significantly more likely to exhibit the homozygous ccr5-32/ccr5-32 genotype compared to a healthy control group . moreover , ccr532 homozygosity in this study was associated with significantly increased hcv viral loads and cd8 + t lymphocyte counts in the peripheral blood . thus , the results of this study would suggest that individuals with a ccr532/ccr532 genotype display an increased susceptibility to hcv infection . , it has been speculated that increased ccr532-frequency may be a specific characteristic of haemophilic patients with chronic hepatitis c but without hiv infection - and rather reflects resistance to hiv-1 than increased susceptibility to hcv . however , a detailed statistical analysis showed that the high frequency of ccr532 in chronic hepatitis c reported by woitas et al . could not be explained by the hiv - mediated selection pressure alone . alternatively , the strategy of patient selection in the woitas study ( haemophilia versus chronic liver disease ) or the analysis of heterogeneous cohorts ( stage and duration of infection , infecting hcv genotype , demographic factors ) might explain these discrepant results . this was examined in two independent largely homogeneous cohorts of hcv - infected women with a known source of infection . in the late 70s these women were infected by anti - d immunoglobulin contaminated with hepatitis c virus ( hcv ) genotype 1b from a single erythrocyte donor administered for prophylaxis of rhesus isoimmunization throughout east germany and ireland , respectively . in contrast to the data published by woitas and co - workers the ccr532 mutation was associated with spontaneous elimination of the virus in the irish anti - d cohort . however , in the eastern german " anti - d cohort , " we found carriers of the ccr532 polymorphism to be significantly more likely to develop chronic infection than women with a homogeneous wild - type genotype ( nattermann et al . , aasld 2009 ) . similar discrepant results have been published regarding a possible association between the ccr532 polymorphism and the degree of the hcv - associated hepatitis . data obtained in the irish " anti - d cohort "   and in two other studies   showed a less pronounced hepatic inflammation in carriers of the ccr532 mutation as compared to patients with a homozygous wild type . however , these results could not be confirmed in other publications [ 36 - 38 ] . in contrast to these controversial data , it is widely accepted that the ccr532 mutation does not affect response to standard combination therapy with pegylated interferon and ribavirin . although the ccr532 polymorphism was associated with a significantly poorer response to monotherapy with standard interferon , no study could confirm a similar effect for patients treated with pegylated interferon in combination with ribavirin . recently , dolan et al . published a very elgant and comprehensive study which might provide some explanations regarding the controversial data on the role of ccr5 in hepatitis c as this work shed light on the complexity of such associations . in this study different cohorts of hiv - positive and hiv - negative persons were analyzed with regard to polymorphisms in the ccr5 gene and the gene of the ccr5 ligand ccl3l1 . ccr5 is an important co - receptor for hiv and earlier studies demonstrated that the ccr5d32 mutation blocks infection of cd4 lymphocytes . dolan et al . identified another mechanism by which ccr5 in association with its ligands affect the course of hiv infection . in this work the study subjects were classified into three genetic risk groups ' ( grgs ) based on variation in ccr5-ccl3l1 genotypes that are associated with risk of acquiring hiv infection and on hiv replication . interestingly the authors could show a direct association of these grks with the cell - mediated immune response . as a marker they determined the delayed - type immune response ( type iv ) , which is a common ' readout ' of cellular immunity . this immune reaction is based on activation of th1 lymphocytes induced by a soluble antigen which in turn results in activation of macrophages . a typical example is the tuberculine test which induces an immune reaction of pre - sensitized t - lymphocytes after inoculation of tuberculine into the skin . dolan and co - workers showed an increased type - iv immune response in those grgs associated with a delayed disease progression . thus , the authors concluded that ccr5 and its ligands not only interfere with viral entry of hiv into the cell but also affect anti - viral responses via modulating cellular immunity . the complexity of these associations was further emphasized by the observation that the ccr5 haplotype ( hhg*2 ) comprising the 32-mutation ( both homozygous or in combination with another specific haplotype ( hhe ) ) is a predictor of a weak cell - mediated immune response and a rapid progression of hiv infection . however , the same ccr5 hhg*2 haplotype in combination with the ccr5 hhc haplotype was associated with a slower progression of infection and possibly with a stronger immune response . for instance , variations of the ccl3l1 gene have recently been shown to affect hcv infection . moreover , ahlenstiehl et al . could show a significantly decreased hcv - specific ifn- response of cd8(+ ) t - cells in carriers of the ccr532 allele as compared to cells from patients with a homozygeous wildtype genotype . this finding suggests the ccr532 polymorphisms to possibly affect cellular immune responses in hcv infection . in summary there is clear evidence for a critical role of the ccr5 receptor and its ' ligands for the regulation of immune response which might also play a role in hcv infection . however , further studies with larger number of patients and a more detailed genetic analysis are necessary to precisely define the role of ccr5 in hcv infection . the authors have no commercial or other association that might pose a conflict of interest . this work was supported by the h. w. and j. hector foundation [ grant number m42 ] .