Several studies have identified specific genetic factors that play an important role in the persistence of HCV infection (41
). It was also observed previously that some HLA alleles clearly influence the resolution of other viral infections (1
). Thus, HLA molecules have been the focus of numerous studies for establishing possible associations with the persistence or the elimination of HCV (9
). Some associations between certain KIRs with their HLA ligands and the progression of HCV infection were also described previously (26
In the present study, we analyzed the influence of KIRs on the response to combined treatment. While the number of patients was relatively small, we considered the homogeneity of the group important. In spite of these limitations, we observed that KIR2DL3 was associated with a sustained viral immune response, while KIR2DL2 was clearly correlated with a nonresponse. Furthermore, we found that KIR2DL3/KIR2DL3-HLA-C1C1 was associated with a sustained virological response, whereas KIR2DL2/KIR2DL2-HLA-C1C2 had a significantly increased frequency in the NR population.
Previous studies suggested a model in which KIR-HLA combinations inhibit NK cells with different intensities (44
). According to this model, KIR2DL1-HLA-C2 has the strongest capacity of inhibition, followed by KIR2DL2-HLA-C1 and, finally, by KIR2DL3-HLA-C1. The weaker inhibition of KIR2DL3 may result in a greater activation of NK cells and, consequently, a more efficient resolution of viral infection. The effects of additional NK-activating receptors, such as NKG2D, may lead to a higher efficacy of control against HCV infection. The two KIR2DL1 (present in 98% of the individuals) and KIR2DL2 receptors may, however, induce a more intense inhibition of NK cells and therefore reduce the efficacy of resolving HCV infection. Moreover, the different KIR2DL-HLA-C interactions may further transmit inhibitory signals with different strengths (37
In agreement with those studies, we suggest that the KIR2DL3/KIR2DL3-HLA-C1C1 genotype combination influences the generation of a sustained virological response, since the inhibitory signals produced by KIR2DL1 and KIR2DL2 are absent. Individuals who carry the KIR2DL3/KIR2DL3-HLA-C1C1 genotype more effectively activated NK cells in response to the administration of Peg-IFN-α during treatment, although NK cell functions have been impaired during chronic HCV infection (15
). Furthermore, several studies described HCV mechanisms that inhibited the responses of NK cells and were correlated with the establishment of a chronic infection (17
). Nevertheless, recent findings demonstrate that a sustained response to combined treatment for patients with chronic HCV infection is closely associated with increased numbers of NK cells in the liver (49
). Other KIR2DL-HLA genotypes have at least one stronger inhibitory signal, and their response to treatment was less effective. Within these genotypes, we suggest that the KIR2DL2/KIR2DL2-HLA-C1C2 genotype has the most inefficient response to treatment, because cumulative inhibitory signals are produced by KIR2DL1 and KIR2DL2. This stronger inhibition could be enhanced by treatment because Peg-IFN-α induces the expression of HLA class I molecules (38
) and favors the interaction between the infected cells and NK cells.
We further observed that the homozygous KIR2DL3 allele in combination with homozygous HLA-C1 was found significantly more frequently in patients who responded to antiviral treatment. The nonresponding patients had a higher frequency of the homozygous KIR2DL2 allele with its heterozygous ligand, supporting our hypothesis. As previously mentioned, Khakoo et al. (21
) described that the presence of the homozygous KIR2DL3 allele and its ligand is correlated to the spontaneous clearance of HCV infection. Our study shows a similar association, but in this case, KIR2DL3/KIR2DL3-HLA-C1C1 is significantly associated with a complete response to antiviral therapy, while the presence of the KIR2DL2/KIR2DL2-HLA-C1C2 genotype correlates with an inadequate response to the treatment and with persistent viral RNA. Despite the observation that the KIR2DL2/KIR2DL2-HLA-C2C2 genotype carries the strongest inhibitory signal mediated by KIR2DL1-HLA-C2, we did not detect statistical differences related to a nonresponse to treatment. Possible explanations include its low frequency in our population and/or the absence of an additional KIR2DL2-HLA-C1 inhibitory signal. Moreover, the bound peptides in MHC class I play an important role in the balanced recognition of NK cells, and the level of KIR2DL1 recognition of this complex may be reduced by some modified peptides during tumor transformation or viral infections (2
The monitoring of HCV RNA levels in serum throughout the treatment period revealed a high percentage of patients carrying KIR2DL3/KIR2DL3-HLA-C1C1 who exhibited a complete response. In contrast, the majority of individuals carrying the KIR2DL2/KIR2DL2-HLA-C1C2 genotype were unable to clear HCV RNA. These data also suggested that treatment in the presence of the KIR2DL2/KIR2DL2-HLA-C1C2 genotype will be less effective in resolving HCV infection.
Analysis of the risk factors in the NR to the treatment showed significant associations only with BMI, the HCV genotype, the KIR genotype, and the KIR-HLA genotype. Previous studies have shown that HCV genotypes influence the response to treatment (50
). For example, HCV genotype 1 is associated with a poor response to antiviral treatment (36
), similar to our results. Several studies suggested that HCV genotype 1 is more resistant to treatment due to the interactions of certain viral proteins, such as NS5A, with the IFN-α signaling pathway (35
). In fact, five HCV-infected patients carrying the KIR2DL3/KIR2DL3-HLA-C1C1 allele did not resolve their infections after therapy in our study, which suggests that additional modalities for resolving HCV infections are warranted. On the other hand, antiviral treatment is usually efficacious against HCV genotypes 2 and 3 and justifies a shorter treatment schedule (8
T lymphocytes, as NK cells, are crucial in the defense against viral infections. With regard to CD8+
T lymphocytes and HLA class I molecules, several studies indicated a central association with the resolution of viral diseases (33
). On the other hand, CD8+
T lymphocytes can express KIRs, and the signals from these receptors can contribute to the control of viral infections (5
In conclusion, the balance of activating and inhibitory signals on NK cells and CD8+ T lymphocytes, which is modulated by treatment and conditioned by genetics, helps to define the antiviral response. In addition to the viral genotype, KIRs play an important role in the immune response against HCV and may be key factors that modulate the progression of the infection and the response to treatment.
Despite the small number of subjects included in this study, we were able to demonstrate significant effects of KIRs and their ligands on the response to treatment of chronic HCV infection. Nevertheless, additional genetic and functional studies will be necessary in order to clarify the involvement of KIRs in HCV infection.