**3. Anti-HCV immunity in HIV/HCV coinfection**

in the prevalence of HIV/HCV coinfection. Its level among drug users reaches 93% [12]. The problem is complicated by the rise in non-AIDS-defining morbidity and mortality in HIV/

There is considerable evidence that HIV infection adversely affects the course of a hepatitis C infection. When HIV/HCV coinfection is compared with HCV monoinfection, a more rapid fibrosis [15, 16] and liver cirrhosis [16, 17] are observed. Coinfected subjects also have an increased risk of hepatocellular carcinoma, which occurs at an earlier age and in a shorter time interval after HCV infection [18–20]. It was found that HIV/HCV-coinfected patients compared to HCV-monoinfected patients were more resistant to interferon therapy. In HIV-seronegative subjects infected with HCV genotype 1, 50–80% can achieve a complete recovery. However, in HIV-seropositive individuals coinfected with the same HCV type, interferon therapy is successful only in 20–35% of patients [21]. This accounts for the increased mortality rate among HIV-/HCV-coinfected patients when compared with HIV-monoinfected patients [22, 23].

Less is known about the effect of hepatitis C on the natural course of HIV infection. Among the negative influences, one can point to direct viral effects, hepatocyte destruction by immunocompetent cells, hepatic cell apoptosis, immune activation, and specific antiviral immune response alterations [24–26]. The complexity of the problem is largely due to the lack of knowledge about the biology of both HIV and HCV. It remains unknown whether the viruses

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/

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

interact with each other and in what ways that interaction might be expressed.

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

HCV coinfection.

HCV-coinfected subjects [13, 14].

46 Advances in HIV and AIDS Control

Protection against HCV is implemented by various factors with an important role for interferons, natural killer (NK) cells, neutralizing antibodies, and T-lymphocytes. Type I interferons (IFN-α and IFN-β) and type III interferon (IFN-λ) are synthesized in response to the virus and induce interferon-stimulated gene (ISG) expression [62, 63]. In the cytosol, the pathogen's RNA is detected by the RIG-I (retinoic acid-inducible gene I) sensors, protein kinase R, and MDA5 (melanoma differentiation-associated protein 5). The first two mediate the interferon response at the early stages of the disease, and the third one mediates at the later infection phase [64, 65]. In endosomes, the virus is primarily detected by Toll-like receptor 3 (TLR3) that also triggers the IFN production and the ISG expression [66]. In hepatocytes of HCVinfected patients, the viral RNA and ISGs' mRNA are detected simultaneously, which confirms the connection between the cell genetic response and the presence of the pathogen [67]. The result of the activated ISG status in HCV infection leads to viral replication inhibition [68, 69]. However, prolonged ISG expression has a negative effect on the process of HCV spontaneous elimination [70, 71] and on the results of interferon and ribavirin combination therapy [72, 73].

NK cells play an important role in the pathogenesis of an HCV infection. It was found that in the healthy liver they represent the majority of the innate immune cells [74]. In the acute phase of the disease, NK cells affected by the virus are activated, produce IFN-γ, and perform cytotoxic functions [75]. In the chronic infection phase, IFN-γ and tumor necrosis factor (TNF)-α synthesis are reduced [76–78] even though the NK cell cytotoxic potential remains high [79, 80]. Since the protective effect of IFN-γ was demonstrated in HCV-infected hepatoma cells [81] and in experiments with chimpanzees given primary and repeated infections [82], it is believed that reduced IFN-γ production weakens the NK cell's antiviral activity. Thus, in the chronic stage of HCV infection, in spite of being activated and ready to perform cytotoxic functions, the NK lymphocytes are unable to effectively resist HCV due to the failure of IFN-γ production. However, the saved killing function can produce a positive result. NK cells from HCV-infected subjects are capable of killing activated LSC by NKG2D- and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-dependent apoptosis, which allows them to be considered as active participants in liver fibrosis suppression [83].

**4. Detrimental effects of hepatitis C on the course of HIV infection**

early treatment administration and uninterrupted long-term ART.

that the immune activation is mediated through TLRs [128–130].

nied by the rise in sCD14, sTNFR-I, and IL-6 concentrations.

It is more difficult to assess the effect of hepatitis C on the natural course of HIV infection. One of the parameters characterizing that effect is CD4+ T-cell count reconstitution after the administration of ART. To date, the accumulated data indicate slowing of the CD4+ T-lymphocyte restoration process in HIV-positive subjects coinfected with hepatitis C [35, 105–108]. The rate of CD4+ T-cell counts increases after receiving ART was reduced sevenfold in coinfected individuals compared with HIV-monoinfected patients [35]. The authors also established an association between impaired immunity regeneration and the level of HCV replication. In another study, it was demonstrated that in hepatitis C-positive patients, ineffective ARTmediated restoration affected not only the total CD4+ T-lymphocyte numbers but also their naive subset [106]. However, it should be noted that not all researchers support the idea of the negative effect of HCV coinfection on the treatment-induced CD4+ T-cell response [109, 110]. Still, an extensive multicenter study involving 22,533 patients showed that immune regeneration during ART is slower in coinfected patients, and the lower the nadir CD4+ T-lymphocyte level, the more pronounced the effect [111]. However, as noted in the paper, the differences in the CD4+ T-cell recovery between HIV + HCV+ and HIV + HCV− subjects are canceled by

Immune Disorders in HIV-Infected Patients Coinfected with Hepatitis C Virus

http://dx.doi.org/10.5772/intechopen.76810

49

HIV infection causes severe devastation in the lymphoid structures of the digestive tract. It is accompanied by intestinal epithelial barrier destruction [112, 113] and the entry of microbes and their products into the bloodstream [114]. The increase in intestinal permeability is due to the direct destructive effect of HIV on the intestinal epithelium [115] followed by the development of inflammation and tissue remodeling [116]. Another cause for the pathological changes to the epithelial barrier is the deficiency of lymphocytes producing IL-17 and IL-22 which are necessary to maintain the epithelial lining integrity [117, 118]. To date, the role of microbial translocation in the immune system activation has been well established [119–121]. In addition, it has been shown that the blood levels of lipopolysaccharide (LPS) and soluble macrophage receptor CD14 (sCD14, capable of binding LPS) in HIV-infected patients can be used to predict disease progression and mortality [122–124]. Recently, in a large cohort of non-treated HIV-infected patients, an association between LPS-dependent immune activation and intestinal damage markers in serum was demonstrated [125]. However, a relationship between the immune system activation and viral load in blood was not found. Other data obtained in a study of bacterial-induced immune activation in patients with suppressed viral load also confirm its independence from the HIV load in blood [121, 126, 127]. It is assumed

It is widely accepted that liver cirrhosis compounds microbial translocation from the intestine into the bloodstream. A comparison of sCD14 blood levels in HIV/HCV-coinfected subjects, with varying degrees of liver fibrosis, showed that in patients with higher cirrhosis the soluble receptor concentration was more than in subjects with minimal organ destruction [131–133]. In HIV infection, the role of cirrhosis in the enhancement of the systemic inflammatory process was demonstrated while comparing two variants: compensated and uncompensated inflammations [134]. When uncompensated, a significantly higher level of LPS-binding protein (LBP) was detected in the patients' blood. The increase in the LBP content was accompa-

The role of neutralizing antibodies (nAB) in protection against an HCV infection is not yet sufficiently understood. Based on known cases of spontaneous recovery before nAB emerge [84] and based on the ability of some patients with hypogammaglobulinemia to control the infection [85, 86], it could be concluded that the humoral immune response does not determine resistance to the disease. At the same time, there is evidence of a protective function for antibodies directed against HCV surface proteins. HCV envelope glycoprotein E1 and glycoprotein E2 seroconversion is usually observed a few weeks after an infection [87]. The ability of viral envelope-specific antibodies to block the infectious process was demonstrated in chimpanzees [88, 89] and in mice with genetically humanized liver [90, 91]. The emergence of nAB in the acute phase of HCV infection is accompanied by an alteration in the virus and its escape from immune control [92]. The authors also showed that despite the increased virus flexibility, high antibody titers significantly increase the chance for clearance of the infection. The acute-phase nAB titers are usually low in patients subsequently entering the chronic stage of the disease.

As was established in monkeys with induced CD4+ or CD8+ T-cell deficiency [93, 94], T-lymphocytes play an important role in the development of hepatitis C. It should be noted that the HCV-specific T-cell response usually develops 2–3 months after the infection [95, 96], although according to some authors such a "slow" reaction has little effect on the disease outcome [84]. It seems that the quality of the immune response achieved by CD4+ and CD8+ T-cells is a more important factor [97, 98]. It was found that in the acute phase of the infection, patients spontaneously clearing HCV compared to subjects in whom the disease became chronic had a more robust CD4+ T-lymphocyte response, which manifested in more active proliferation and cytokine (IFN-γ, TNF-α, and IL-2) production [99–102]. Later, it was found that the expression of PD-1 (programmed cell death protein 1) and CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) inhibitory molecules was increased on the surface of CD4+ T-cells in patients chronically infected with HCV [103]. Blocking of PD-1 ligand (PD-L1/ PD-L2), IL-10, and TGF-β1 in cultured lymphocytes isolated from the blood of these patients increased the virus-specific expansion of CD4+ T-lymphocytes. Neutralization of IL-10 and TGF-β1 enhanced the synthesis of IFN-γ, IL-2, and TNF-α. Further studies revealed that IL-21-producing CD4+ T-lymphocytes are lost in individuals with a chronic hepatitis C infection [104]. It has also been demonstrated that the deficiency of Th17 cells synthesizing IL-21 limits the HCV-specific CD8+ T-lymphocyte function and survival. The inability of CD4+ and CD8+ T-cells to control viral replication leads to their exhaustion. According to the authors, in chronic HCV infection, the increase in regulatory T-cell number and activity is aimed at suppressing an ineffective immune response and reducing inflammation. The other side of that process is fibrosis intensification. Thus, based on the above data, one can conclude that CD4+ T-lymphocytes are the key cells in protection against HCV. Hence, it becomes clear why a low CD4+ T-cell count is a negative predictor for liver fibrosis development in HIV-/HCVcoinfected patients.
