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Intra-hepatic messenger RNA levels for interferons and related genes in hepatitis C virus/HIV co-infected patients
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AIDS: Volume 18(4) 5 March 2004 pp 691-692
Abbate, Isabellaa,c; Cappiello, Giuseppinac; Rosati, Silviab; Tocci, Guidob; Antonucci, Giorgiob; Solmone, Mariacarmelaa; Longo, Robertac; Spanò, Albertoc; Capobianchi, Maria Rosariaa
aLaboratory of Virology, b1 Clinical Ward, and cMicrobiology and Virology Service, 'S. Pertini' Hospital, Rome, Italy, Rome, Italy.
Sponsorship: Financial support was obtained from the Italian Ministry of Health, Ricerca Corrente e Finalizzata.
Received:
Intra-hepatic levels of mRNA for IFN-a, IFN-g, IFN type 1 receptor (IFNAR-1) and PKR were determined in hepatitis C virus (HCV)/HIV co-infected and HCV mono-infected patients. In co-infected patients, IFN-a mRNA was upregulated and correlated with HIV-1 viraemia. IFN-g, IFNAR-1 and PKR mRNA were detected in mono-infected, but not in co-infected patients. These findings suggest that in HCV/HIV co-infected individuals the ability to respond to IFN-a is impaired, probably because of the absence of its receptor.
Hepatitis C virus (HCV) infection runs a more rapid and severe course of liver disease in HIV-1-co-infected patients [1]. Although it is likely that an imbalanced immune response could contribute to this phenomenon, the underlying pathogenetic events have not been fully elucidated [1,2]. Since new therapeutic antiretroviral regimens have prolonged the survival time of HIV-infected patients, treatment of HCV has become a major challenge in these individuals. In this respect, a better understanding of the pathogenetic events, and identification of predictive parameters able to design a more appropriate therapeutic regimen are highly desirable.
It was recently shown that in HCV-infected patients intra-hepatic messenger RNA levels for IFN and IFN-related genes are altered compared with those found in patients with non-infectious liver disease. In particular, IFN-a and IFN-b mRNA levels were lower, and IFN-g mRNA levels were higher in liver biopsies from HCV-infected, compared with non-alcoholic steato-hepatitis patients. Moreover, in HCV-infected patients IFN-g mRNA levels were correlated with those of IFN type I receptor (IFNAR-1) and IFN regulatory factor 1, probably as a result of a coordinated induction. It is noteworthy that high IFN-a and IFN-b mRNA levels were associated with low staging, suggesting a possible protective role of IFN-a and IFN-b against fibrosis [3].
In this study we analysed mRNA levels for IFN-a, IFN-g, IFNAR-1 and PKR in liver biopsies of HCV/HIV-co-infected patients to compare their levels with those found in singly HCV-infected individuals. To this aim, liver biopsies from 20 HIV/HCV co-infected patients and from 24 HCV-infected patients, similar for demographic features, HCV viral load and genotypes, as well as for liver histology, were analysed. None of the patients had previously been treated with IFN. Thirteen co-infected patients were on triple combination antiretroviral treatment at the time of biopsy: 10 patients were receiving two nucleoside reverse transcriptase inhibitors (NRTI) plus one protease inhibitor, two were receiving two NRTI plus one non-NRTI, and one patient was receiving a combination of three NRTI.
Total RNA was extracted from liver biopsy, and analysed by limiting dilution reverse transcriptase-polymerase chain reaction, by using primers specific for IFN-a, IFN-g, IFNAR-1 and PKR, as previously described [3]. Possible relationships between mRNA levels for IFN and HCV and HIV viral load, CD4 cell counts and liver damage were also investigated.
The results, shown in Table 1, indicate that in HCV/HIV-co-infected patients intra-hepatic IFN-a mRNA levels are upregulated compared with HCV-mono-infected patients, whereas IFN-g, IFNAR-1 and PKR are profoundly downregulated, because in all biopsies from co-infected patients they were under the detectable levels. We further observed a positive correlation between IFN-a mRNA levels and the HIV-RNA viral load (r = 0.526, P = 0.018, in Spearman rank sum test). In co-infected patients, similar mRNA levels for IFN-a were found in patients with HCV viraemia higher or lower than 500 000 IU/ml, and they were not related to alanine aminotransferase levels or CD4 cell counts. Furthermore, no different IFN-a mRNA levels were observed in co-infected patients with absent/mild versus moderate/severe fibrosis. This is at variance with mono-infected patients, in whom IFN-a mRNA levels were higher in patients with a lower extent of fibrosis [3].
The upregulated IFN-a mRNA levels in the liver of HCV/HIV-co-infected patients and their relationship with the HIV viral load are in agreement with the chronic activation of the IFN system observed in HIV-infected patients, leading to the presence of circulating IFN-a [4].
In the present study we also showed that, in the liver of HCV/HIV patients, mRNA for IFN-g, IFNAR-1 and PKR are virtually absent. As IFN-g is one of the main upregulators of IFNAR-1 [5] it is likely that the absence of mRNA for both factors in the liver of co-infected patients may be causally related.
The presence in these patients of upregulated IFN-a mRNA, together with a parallel absence of mRNA for IFNAR-1 indicate that, in spite of a strong activation of IFN-a expression, driven presumably by HIV, there is an impaired ability to respond to IFN-a action, because of the lack of expression of its receptor. This is also supported by the virtual absence of mRNA for the main IFN-a effector protein (PKR).
These results may have important implications regarding the pathogenesis of the liver damage and therapeutic regimens to be used in co-infected patients.
For the first issue, data from our previous study suggest that IFN-a may exert a possible protective role against the development of fibrosis [3]. In co-infected patients, in whom the response to IFN-a seems to be impaired, despite upregulated IFN-a mRNA levels, the reported accelerated progression towards liver fibrosis may be accounted for by the inability to mount a proper response.
For the second issue, intra-hepatic expression levels of type I IFN receptor have been related to the rate of sustained response to treatment in HCV-infected patients [6,7], and the presence of soluble IFN receptors in HCV-infected patients is considered a negative prognostic factor for therapy outcome [8]. In this respect, although initial data indicated a similar rate of response to IFN therapy in mono-infected and co-infected patients, a recent study indicated a reduced response to combined regimens of IFN plus ribavirin in the latter [9]. In view of this finding, it would be necessary to carry out a careful re-assessment of the optimal therapeutic regimens to be used in co-infected patients, which would be able to circumvent their intrinsic inability to mount an adequate response to IFN-a in the liver.
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