**2. Liver fibrosis in HIV/HCV coinfection**

Evidence indicates that the HCV viral load is lower in hepatitis C-monoinfected patients when compared to HIV/HCV-coinfected patients [27, 28]. Similar results were obtained when estimating the viral load in hepatic tissue [29]. In addition, multiyear cohort studies state that in patients with hepatitis C the HCV RNA blood level significantly increases after exposure to HIV [30, 31]. HCV replication enhancement in coinfection is attributed to both the development of immunodeficiency and the direct impact of HIV. While attempting to determine the mechanism(s) of these effects, it was shown that inactivated HIV or its component (gp120) can intensify viral replication in HCV-infected hepatoma cells in vitro [32]. This effect of HIV was shown to be due to transforming growth factor-beta 1 (TGF-β1) synthesis (antibodies against the cytokine blocked the HCV replication enhancement). Researchers also noted that HIV engages CCR5 or CXCR4 co-receptors for the related intracellular signal induction. Those data are significant not only for demonstrating the ability of HIV to increase HCV replication (with a monoinfection of hepatitis C, viral load is usually not associated with the disease severity) but also for illuminating the possible pathogenetic mechanism of fibrosis in HIV/ HCV coinfection.

In many studies, HIV/HCV-coinfected patients demonstrated an inverse correlation between the CD4+ T-cell count and the HCV viral load [33–37]. Moreover, in those patients, low CD4+ T-lymphocyte quantity was used as a liver fibrosis predictor [34, 38, 39]. This suggests a negative impact of HIV infection on the course of hepatitis C through the development of CD4+ T-cell deficiency. It should be noted that a decrease in the CD4+ T-lymphocyte count is also found in those monoinfected with HCV. Indeed, the majority of HIV-seronegative subjects with liver cirrhosis have a reduced CD4+ T-cell count [40, 41]. Most researchers state that HIV infection, accompanied by a profound depletion in the CD4+ T-lymphocyte pool, is a prominent mediator of the accelerated liver fibrosis development in HIV-/HCV-coinfected people [42–44]. Based on those results and the opinions of leading specialists, the European AIDS Clinical Society recommends the early administration of highly active antiretroviral therapy (ART) to HCV-coinfected patients not only to optimize their hepatitis C management but also to slow down the development of fibrosis [45].

The main cellular element involved in the process of hepatic tissue fibrosis is the liver stellate cell (LSC) [46–49] located around the sinuses and usually not showing high activity until the organ is damaged [50, 51]. However, various destructive processes in the liver are accompanied by the reaction of hepatocytes, endotheliocytes, and Kupffer cells to produce various humoral factors [52]. Of those, TGF-β1 [53, 54] and PDGF (platelet-derived growth factor) have the most pronounced effect on LSC [52, 55]. Both cytokines induce LSC activation and differentiation into myofibroblast-like cells, which actively synthesize extracellular matrix proteins [56]. However, it should be noted that TGF-β1 and PDGF blood concentrations (as opposed to analyzing the hyaluronic acid or hepatocytes' growth factor content) have no high diagnostic value for the detection of fibrosis [57–60]. Moreover, it has recently been established that HIV influences the liver by infecting hepatocytes and liver stellate cells [61].
