miRNA expression profiles in liver grafts of HCV and HIV/HCV‐infected recipients, 6 months after liver transplantation

Abstract

In hepatitis C virus (HCV)/human immunodeficiency virus (HIV) co‐infected patients, HIV enhances HCV replication and liver damage. Several microRNAs (miRNAs), active in pro‐fibrotic and inflammatory pathways, have been implicated in the pathogenesis of this phenomenon. However, these miRNAs have been tested only in explanted cirrhotic livers, when the liver damage has become chronic and irreversible. No data are available on the early phase of viral infection, such as early after liver transplantation (LT). In the present study, the expression of miR‐101, miR‐122, miR‐155, miR‐192, miR‐200c, miR‐338, and miR‐532 was determined by quantitative real‐time polymerase chain reaction in liver biopsies of HCV (n = 19) and HCV/HIV‐infected (n = 20) LT recipients, as well as in a control group (n = 18) of noninfected patients, transplanted for alcoholic cirrhosis. The timing of liver biopsy was 6 months post‐LT. None of the patients was treated with direct‐acting anti‐HCV drugs. All co‐infected recipients had suppressed HIV viral load. Grading and staging were assessed according to the Ishak Classification. HCV and HIV viral load were measured in the sera. miR‐101 (p = .03), miR‐122 (p = .012), and miR‐192 (p = .038) were significantly downregulated in HCV/HIV co‐infected and HCV mono‐infected recipients when compared with noninfected recipients, and such downregulation was more pronounced in co‐infected ones. Moreover, in co‐infected recipients but not in mono‐infected ones, miR‐101 inversely correlated with the peripheral HCV‐RNA levels (r = .41, p = .04) and miR‐122 inversely correlated with peripheral HCV‐RNA levels (r = .49, p = .03) and with the histological grading (r = .51, p = .02). In conclusion, as early as 6 months after LT, the presence of HIV‐HCV co‐infection enhanced a significant downregulation of certain miRNAs that showed a direct correlation with HCV viral load and liver inflammation.

Reinfection of Transplanted Livers in HCV- and HCV/HIV-Infected Patients Is Characterized by a Different MicroRNA Expression Profile

“…The introduction of both HAART for HIV-1 infection and DAAs against HCV has significantly improved the prognosis of HIV/HCV co-infected patients with ESLD [ 1 , 2 , 3 , 7 , 8 , 9 , 10 , 11 ]. However, reinfection of graft is practically inevitable in HCV positive transplanted patients and the presence of co-infection with HIV makes the evolution towards fibrosis more rapid [ 4 ].…”

“…Indications to liver transplantation were identical in HCV mono-infected and HCV/HIV-coinfected patients, as previously reported in [ 1 ]. Exclusion criteria included split liver graft, HBV positivity, coexisting autoimmune hepatitis, post-LT surgical or immunologic complications, treatment with DAA-HCV drugs before LT or within 6 months post-LT, unavailability of a liver biopsy obtained at 6 ± 1 months post-LT, a biopsy core containing less than 11 portal spaces, pathologic features of graft rejection or cholangiopathy on liver biopsy [ 2 ]. Thus, 19 HCV mono-infected and 20 HCV-HIV coinfected recipients were selected on the basis of the same MELD score, graft steatosis and total ischemia time [ 10 , 20 ].…”

“…Thus, 19 HCV mono-infected and 20 HCV-HIV coinfected recipients were selected on the basis of the same MELD score, graft steatosis and total ischemia time [ 10 , 20 ]. Recipient age was not considered for the matching because the epidemiology of HCV infection and HCV/HIV co-infection is significantly different in terms of age [ 2 ]. Liver biopsies (LB) were formalin-fixed paraffin-embedded (FFPE).…”

“…Since the introduction of highly active antiretroviral therapy (HAART), human immunodeficiency virus type 1 (HIV-1) infection is not, anymore, an exclusion criterion for liver transplantation (LT) in patients with a Hepatitis C virus (HCV)-related end stage disease [ 1 , 2 , 3 ]. This latter is the consequence of chronic inflammation, immune activation, and immune senescence due to HCV infection [ 4 , 5 ].…”

“…Reinfection of human liver grafts represents, instead, a unique and quite unexplored model to study early stages of liver disease and to investigate the possible interaction of HCV and HIV. In this regard, we have recently demonstrated that, as early as 6 months after liver transplantation, grafts of HCV and HCV/HIV recipients differ in the expression of clinically relevant selected miRNAs, suggesting a possible connection between specific miRNA deregulation, viral load and fibrosis [ 2 ].…”