*Purpose: The ability of the CMV to infect the endothelial cells (ECs) is critical. CMV can increase EC adhesion, permeability, and create a pro-inflammatory environment that can promote angiogenesis. This study aimed to show both the direct and indirect effects of CMV on the development of LF.

*Methods: CMV positive 24 patients (Group 1) and CMV negative 45 patients (Group 2) were included in the study. Number of AR episodes were recorded. All biopsies were scored and immunostained with α-SMA, TNF-α, TGF-β, and CD31. Activated HSCs determined by the expression of α-SMA and angiogenes was highlighted with CD31. The development of LF during 18 months was evaluated in follow-up biopsies.

*Results: The mean number of AR episodes were higher in Group 1 (1.45±1.2) compared to Group 2 (0.55±0.7) (p=0.001). The degree of HSC activation, angiogenesis, liver TGF-β and TNF-α expression were higher in Group 1 compared to Group 2 (p<0.001). The degree of angiogenesis showed a positive correlation with the degree of leukocyte infiltration, HSC activation, liver TGF-β and TNF-α expression (p<0.001). LF was found to be higher in Group 1 (87.5%) compared to Group 2 (33.1%) (p<0.001). Also, a significant relationship was found between the groups in regards to the fibrosis score (p<0.01). LF showed a positive correlation with the degree of leukocyte infiltration, angiogenesis, HSC activation, liver TGF-β and TNF-α expression (P<0.001). Overall 10-year graft survival was 91% and 67% for CMV negative and positive patients, respectively (p=0.008).

*Conclusions: We showed that CMV infection plays multiple roles on the induction of angiogenesis and therefore the development of LF. CMV increases the incidence of AR episodes characterized by inflammation, and EC activation which in turn leads to both the development of HSC activation and progressive cytokine and growth factor expression with proangiogenic action that stimulates angiogenesis.

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