Survival and HLA-B*57 in HIV/HCV Co-Infected Patients on Highly Active Antiretroviral Therapy (HAART).

BACKGROUND AND AIMS: HLA class I alleles, in particular HLA-B*57, constitute the most consistent host factor determining outcomes in untreated HCV- and HIV-infection. In this prospective cohort study, we analysed the impact of HLA class I alleles on all-cause mortality in patients with HIV-, HCV- and HIV/HCV- co-infection receiving HAART. METHODS: In 2003 HLA-A and B alleles were determined and patients were prospectively followed in 3-month intervals until 2013 or death. HLA-A and B alleles were determined by strand-specific oligonucleotide hybridisation and PCR in 468 Caucasian patients with HCV- (n=120), HIV- (n=186) and HIV/HCV-infection (n=162). All patients with HIV-infection were on HAART. In each patient group, HLA class I-associated survival was analysed by Kaplan-Meier method and Cox regression analysis. RESULTS: At recruitment the proportion of patients carrying a HLA-B*57 allele differed between HIV- (12.9%) and HCV-infection (4.2%). Kaplan Meier analysis revealed significantly increased mortality in HLA-B*57-positive patients with HIV-infection (p=0.032) and HIV/HCV-co-infection (p=0.004), which was apparently linked to non-viral infections. Cox logistic regression analysis confirmed HLA-B*57 (p=0.001), serum gamma-glutamyltranspeptidase (p=0.003), serum bilirubin (p=0.022) and CD4 counts (p=0.041) as independent predictors of death in HIV-infected patients. CONCLUSION: Differences in the prevalence of HLA-B*57 at study entry between HIV- and HCV- infected patients may reflect immune selection in the absence of antiviral therapy. When patients were treated with HAART, however, HLA-B*57 was associated with increased mortality and risk to die from bacterial infections and sepsis, suggesting an ambiguous role of HLA-B*57 for survival in HIV/HCV infection depending on the circumstances.

Differential expansion of T-cell receptor variable beta subsets after antigenic stimulation in patients with different outcomes of hepatitis C infection.

Persistent antigenic stimulation during chronic hepatitis C may alter the T-cell receptor variable chain beta (TCR BV) repertoire as well as the cytokine responses of hepatitis C virus (HCV)-specific T lymphocytes. We analysed the distribution of the TCR BV subsets 2.1, 3.1, 5.1, 6.1, 8, 13.1, 13.6, 14.1, 17.1, 21.3 in relation to intracytoplasmic expression of interleukin-2, interferon-gamma, interleukin-4 and interleukin-10. Using flow cytometry, CD45RO+ memory T cells of 27 patients with chronic hepatitis C, eight patients with resolved HCV infection and 16 non-HCV-related controls were studied with and without stimulation by the HCV core, NS3, NS4, NS5a and NS5b proteins. Patients with chronic and resolved hepatitis C differed by larger basal TCR BV2.1+, BV6.1+, BV17.1+ and BV21.3+ subsets in chronic hepatitis C, which were correlated to the numbers of T cells with spontaneous interleukin-2 and interferon-gamma production (r=0.51-0.73, P<0.05). Upon HCV-specific stimulation these subsets did not expand, whereas a marked in vitro expansion of TCR BV8+ T cells in response to all HCV proteins was selectively noted in chronic hepatitis C (P<0.05). This expansion of TCR BV8+ memory T cells was significantly correlated to HCV-induced interleukin-10 expression (r=0.58-0.98, P<0.01). Thus, differential involvement of selected TCR BV subsets may be related to the outcome of HCV infection.