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

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

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 INR subjects are characterized not only by a deep CD4+ T-lymphocyte deficiency but also by decreased IL-2 production. Earlier, it was demonstrated [157] that through the secretion of this cytokine, T-cells can stimulate the natural killer cell's antifibrotic activity (realized through the killing of liver stellate cells). Thus, in HIV/HCV-coinfected INR patients, the IL-2 deficiency may be regarded as a liver fibrosis-accelerating factor.

In summary, it can be concluded that HIV/HCV-coinfected INRs are characterized by both a CD4+ T-lymphocyte deficiency and reduced IL-2 production which leads to liver destruction and cirrhosis formation. Under such conditions increased intestinal permeability (due to HIV infection) is supplemented by destruction of the hepatic barrier, accompanied by the entry of microbial products into the bloodstream. As a result, despite the ART-mediated HIV replication suppression, a pronounced systemic inflammation develops, leading to non-AIDSdefining diseases. Therefore, in coinfection, not only HIV infection therapy but also hepatitis С treatment should be actively carried out.
