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"We have recently identified the brain cells harboring HCV as macrophages/microglia . In that study, basic brain cell types (macrophages/microglia, neurons, astrocytes, oligodendrocytes) were separated by laser capture microscopy from autopsy brain tissue from two HCV-positive patients. HCV-RNA positive and negative strands were consistently detected only in CD68-positive cells (macrophage/microglia). In a different approach, brain tissue was stained with anti-NS3 monoclonal antibodies, NS3-positive cells were separated by laser capture microscopy and phenotyped by the amplification of cell-specific transcripts. Again, the evidence pointed to CD68-positive cells as the being infected by HCV.
The hypothetical route for CNS infection could be provided by infected macrophages/monocytes, and perhaps also by B cells and T cells ('Trojan horse' mechanism). Although it was long believed that circulating leukocytes are excluded from the CNS, it is now known that all basic groups of leukocytes, T cells, B cells, macrophage/monocytes and natural killer cells, have the ability to enter the brain under certain conditions . Importantly, certain monocyte family members are constantly being replaced as part of normal physiology [56,57], whereas the entry of T cells and B cells appears to be dependent only on the activation state of the leukocyte and not on CNS factors [58,59]. In support of this hypothetical mechanism come observations on the presence of HCV in the cerebrospinal fluid (CSF) from both HIV-positive and HIV-negative patients [60,61]. In a more recent study , we found HCV RNA in the cellular fraction of CSF (eight out of 13 patients), but viral sequences were rarely present in supernatants (two out of 13 patients). Importantly, in half of the patients in whom viral sequences were amplified, the CSF-derived virus was closer to that found in PBMC, than to that circulating in serum, which suggested that it was of lymphoid origin. In two of the latter patients sequences recovered from CSF and serum were classified as belonging to different genotypes. However, they were compatible with the genotype present in PBMC. These findings strongly suggest that the virus found in CSF was derived from peripheral blood leukocytes, and not serum. The presence of differing viral genotypes in serum and lymphoid compartments was also reported by others .
The still hypothetical scenario connecting HCV infection and functional CNS changes could be summarized as follows. HCV can infect PBMC, particularly macrophages, and this process is likely to be facilitated by concomitant HIV co-infection. Infected leukocytes could cross the blood-brain barrier ('Trojan horse' phenomenon) in a process similar to that postulated for HIV-1 infection [63,64]. Subsequently, there could be a secondary spread of HCV to permissive cells within the brain. The primary targets are brain microglia cells, which are essentially tissue-resident macrophages of blood monocytic origin . Infected macrophages and microglia cells could release proinflammatory cytokines, such as TNF-α, IL-1, and IL-6, neurotoxins such as nitric oxide, and viral proteins, which could induce an alteration in brain function leading in turn to neurocognitive dysfunction and depression [66,67]. A similar chain of events seems to be operational in HIV-1 infection [68,69]. However, despite some similarities there is a fundamental difference between HIV-1 and HCV infections, as the latter does not progress into AIDS-type dementia. This is perhaps due to the fact that HCV replication in macrophages is low level and is confined to a limited number of cells ."