HIV-1/HCV co infection : Immunity and viral dynamics

Detta är en avhandling från Stockholm : Karolinska Institutet, Department of Medicine

Sammanfattning: Human immunodeficiency virus-1 (HIV-1) and hepatitis C virus (HCV) are the agents behind two viral epidemics causing huge morbidity and mortality worldwide. HCV infection is a leading cause of end-stage liver disease. Co-infection with HIV leads to faster progression to cirrhosis and lower clearance rate of HCV infection following current standard treatment with pegylated interferon alpha (peg-IFNalpha) and ribavirin. The overall aims of the studies described in this thesis were to gain knowledge of how to best manage HIV/HCV co-infection in clinical practice, to study immunological features in co-infected patients, to search for immunological host factors affecting HCV treatment outcome, and to identify possible predictive markers of treatment response. In paper I we investigated the feasibility of treating HIV/HCV co-infected patients with peg-IFNalpha and ribavirin in a Swedish HIV outpatient clinic. We found that only a small fraction of the patients were suitable treatment candidates when following international guidelines. However, in those treated the response was good and correlated to HCV RNA kinetics during initial treatment. One of the patients, who was among those screened for participation in the abovementioned study, spontaneously cleared her chronic HCV infection. Since this is a very rare event we further investigated the immune response of this patient, as described in paper II. She displayed a low level of T cell activation and a high level of T cell function comparedto HIV/HCV co-infected control subjects, thus resembling a healthy individual. In paper III we investigated the impact of chronic HIV/HCV co-infection and the effects of treatment with peg-IFNalpha and ribavirin on NK cells and on NKT cells by flow cytometry. Conventional NK cells were largely unaffected by the co-infection, with only a slight decrease in perforin content in CD56dim cells and an increased CD56bright immunoregulatory population. In contrast, the NKT cells were severely reduced in the co-infected patients and were not restored by HCV therapy. Interestingly, we observed a significant accumulation of unconventional CD56-CD16+ NK cells in these subjects. The expansion of CD56- NK cells was rapidly reverted when HCV replication was suppressed by HCV treatment. In paper IV, we observed that the CD56- NK cells in HCV infected patients were functionally skewed, with poor IFNgamma production but retained MIP-1beta expression. In addition, we found that pretreatment levels of CD56- NK cells in peripheral blood correlated with peg-IFNalpha and ribavirin treatment outcome. Patients with low levels of CD56- NK cells were more likely to clear the HCV infection, and this was not directly linked to other viral and host factors known to influence treatment outcome. In paper V we measured the chemokine IP-10 in plasma from HIV/HCV co-infected patients. We found that lower pretreatment plasma IP-10 levels were associated with faster clearance of the virus. This effect was more pronounced on the first phase viral reduction (day 0-2), than on the second (day 7-28). In summary, this thesis increases our knowledge of the immune system s interaction with HCV and HIV, and identifies an immunological biomarker that correlates with HCV treatment outcome. In addition, it highlights the need for further implementation of HCV treatment in the HIV/HCV co-infected patient group.

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