**6. Conclusion**

Entry of large amounts of microbial products into the liver can have a negative impact on its function in HIV-infected individuals [135]. Liver cells actively express TLRs [136–139] that can interact with bacterial molecules and cause a marked inflammatory response in liver tissue [140, 141]. However, in experiments, it has been shown that prolonged exposure to LPS leads to a gradual decrease in the hepatocyte's sensitivity and a weakening of its ability to capture the bacterial lipopolysaccharide [142]. This causes a decrease in the detoxification function of the liver in patients monoinfected with HIV. The presence of hepatitis and cirrhosis additionally contributes to the decrease in LPS clearance by hepatocytes [143]. Consequently, in coinfection, microbial products entering the blood should cause strong immune activation. Indeed, the level of immune activation in HIV/HCV coinfection is higher than that in HIV

Activation of CD4+ and CD8+ T-cells is often followed by apoptosis: a phenomenon called "activation-induced cell death" (AICD) [148, 149]. AICD can be achieved through several mechanisms involving T-cell receptor stimulation, CD95, and various cytokines [150]. The role of innate immunity receptors in this phenomenon has also been established. Addition of various TLR ligands to cultured T-lymphocytes from healthy donors induced CD38 expression on CD4+ and CD8+ T-cells in short-term (less than 24 h) cultures [129]. Long-term culture (7 days) with TLR ligands led to a pronounced CD69 expression on CD8+ T-lymphocytes and Ki-67 expression in CD4+ T-cells. In such a case, CD8+ elements retained viability, and cycling CD4+ T-lymphocytes died. The data presented show how CD4+ T-cells, activated by microbial products, can die in HIV/HCV-coinfected patients. It is known that in untreated HIV-infected patients, HCV coinfection increases the apoptosis indices, but that effect is canceled by ART [151]. Later, the same authors found that in HIV/HCV coinfection, CD4+ T-lymphocytes are

A current concern is that as many as 30% of treated HIV-infected patients experience poor CD4+ T-cell restoration despite prolonged suppression of viral replication during ART (discordant immune response). These "immune nonresponders" (INRs) contrast with "immune responders" who recover their CD4+ T-cells to the normal range (>500/μL) while being treated. The discordant immune response is linked to an additional risk of mortality and non-AIDS-defining morbidities [153]. Still, the mechanisms responsible for insufficient CD4+

Our own studies have provided some additional information on the negative impact of hepatitis C on the natural course of an HIV infection. In our Russian cohort, we showed that HCV coinfection is a sufficient risk factor for the formation of a discordant CD4+ T-lymphocyte response to ART [154]. At the same time, we found that in coinfected patients when compared with patients monoinfected with HIV the increase in systemic inflammation was associated with liver damage and destruction of the hepatic barrier that protects against microbial products coming from the intestine [155]. INRs have a higher degree of hepatic tissue destruction and express more sclerosing processes [156]. We also found that HIV/HCV-coinfected

[144, 145] or HCV [146, 147] monoinfection alone.

50 Advances in HIV and AIDS Control

sensitized to Fas-induced apoptosis [152].

**5. HIV/HCV-coinfected immunological nonresponders**

T-cell recovery during ART have not been fully discerned.

In HIV/HCV coinfection, the level of immune activation is higher than in HIV and HCV monoinfections. The transition of immunocompetent cells to the activated state is accompanied not only by their loss through the AICD mechanism but also leads to the development of non-AIDS-defining diseases, especially against the background of ART administration.

It can also be concluded that HIV infection exerts a greater influence on the natural course of a hepatitis C infection than the opposite. The key link in this influence is the depletion of CD4+ T-cells. However, not only CD4+ T-lymphocyte deficiency determines the HIV-negative impact on the development of hepatitis C. Even on the background of ART, HIV infection has a pronounced suppressive effect on NK cell activity against HCV. In HIV/HCV coinfection, a decrease in natural killer cell numbers and their ability to respond to IL-2 is observed. More importantly, the production of IFN-γ by those cells is also significantly impaired [158]. The outcome is the rapid development of liver fibrosis and cirrhosis.

As to changing the course of HIV infection against the background of hepatitis C, many questions remain. It is necessary to identify the main CD4+ and CD8+ T-cell subsets which are affected by HCV infection. In addition, studies of functional changes in T-lymphocytes like exhaustion [159–161], senescence [162–164], and loss of cytokine receptors [165, 166] must occur. It is also important to understand the nature of the immune system activation in HIV/ HCV coinfection which is important in predicting the development of non-AIDS-defining diseases. Solving these issues requires further experimental and clinical research.
