There is a wealth of data generated in the field of HCV mono-infection describing impairment in brain function associated with HCV mono-infection. This literature is relevant as it hints towards mechanisms that may interact with or add to well-defined models of HIV neuropathogenesis (to be discussed in detail elsewhere in this issue). For a more detailed review of the HCV-monoinfection literature readers are referred to Forton et al. (2001
The specific brain targets infected by HCV remain a matter of debate. Letendre et al. (2007)
reported the presence of HCV proteins in brain astrocytes using Western blotting and immunostaining among co-infected patients. More recently, Wilkinson et al. (2008)
examined sections of frontal cortex and subcortical white matter from 12 HCV infected patients (six of whom were co-infected with HIV) and found HCV presence in CD68 cells (macrophages and microglia) and less involvement within brain astrocytes. Of interest is that the HCV phenotype was identical between HCV mono-infected samples and co-infected samples. These findings are consistent with Letendre et al. (2007)
in that both studies demonstrated evidence of HCV antigens in the brain, but they differ in terms of the primary cell populations infected. As described by Wilkinson et al. (2008)
, these differences may be associated with the difference in patient populations or in the differences in methods to determine which cells were primarily infected (use of polyclonal antibodies against the NS5A protein vs. monoclonal antibodies against the NS3 protein).
Nevertheless, the presence of HCV antigens in the brain along with evidence of HCV diversification in the brain (Bagaglio et al. 2005
) suggest that the brain may represent a site of persistent HCV viral replication among co-infected patients. For example, Adair et al. (2005)
demonstrated down-regulation of oxidative phosphorylation genes in the brains of HCV-infected patients. Functionally this finding is of significance as oxidative phosphorylation is a critical source of cell energy and neurons are susceptible to reduced energy sources due to high metabolic rates. As described by Adair, high levels of free radicals in the brain may be produced as a consequence of disruption in energy-dependent calcium homeostasis. The data suggested above suggest that brain infection with HCV could potentially lead to free radical damage. Alternatively, it is possible that presence of HCV in the brain could produce an inflammatory cascade not very different from HIV (Forton et al. 2008
; Morgello 2005
; Paul et al. 2007
A number of MRS studies have demonstrated metabolite abnormalities associated with HCV mono-infection. For example, Forton et al. (2008)
revealed elevations in the myo-ml/creatine (Cr) ratio in the frontal white matter among patients with chronic HCV mono-infection. Increased ml is believed to represent microglial activation and astrogliosis (Bitsch et al. 1999
), and therefore elevations in the ml/Cr ratio may reflect consequences of proinflammatory reactions to the presence of HCV in the brain (Forton et al. 2008
). Of interest is that Forton et al. (2008)
also demonstrate a significant inverted relationship between elevated ml/Cr ratios and working memory performance among patients infected with HCV suggesting that the MRS metabolite disturbance may underlie functional properties of the brain.
Evidence of HCV-mediated inflammation in the brain has been observed by Letendre et al. (2005)
. Specifically, HCV serostatus was found to associate with a range of inflammatory indices (e.g., MCP-1, TNF-alpha and TNFR-II). When all of the inflammatory indices were considered together, HCV status was most strongly associated with increased levels of sTNFR-II levels, and these relationships remained significant after controlling for substance abuse history and HIV serostatus. Collectively these findings suggest a model of HCV-mediated brain involvement characterized by HCV presence in the brain, disruption in metabolic processes/oxidative stress, and pro-inflammatory reactions that lead to impaired neuronal function.
The model defined above is intriguing but it is not without limitations. As described by Letendre et al. (2007)
identification of HCV presence in the brain has proven difficult and this may relate to low rates of viral replication in the brain or the development of antibody complexes or other immunological reactions. Thus the level of HCV in the brain may not be sufficient to drive sustained brain damage, or the virus is present but undetectable. Further, a number of studies of HCV-mono-infected patients have revealed relationships between liver disease and cognition raising the possibility that liver dysfunction may also be related either directly or indirectly to CNS compromise in this population. As noted previously, Perry et al. (2005)
reported a significant relationship between neuropsychological performance and liver fibrosis stage In addition, Hilsabeck et al. (2002
) reported that poor cognitive function among HCV mono-infected patients is associated with increased severity of liver fibrosis.
Most recently, Morgello et al. (2005)
contrasted neuropsychological performance between HIV patients from the MHBB with evidence of HCV in the brain and liver, patients with evidence of HCV only in the liver, and patients with no evidence of HCV in either the brain or the liver. Results revealed that individuals with evidence of HCV in the brain performed significantly worse on Trail Making B compared to individuals without evidence of HCV sequences in the brain. However, neuropathological results revealed a high level of abnormalities among individuals with HCV sequences in the brain and
among individuals with HCV only in the liver. Specifically, both groups exhibited Alzheimer type 2 gliosis in the brain regardless of whether HCV was present in the brain. This latter finding suggests that the brain does not have to be directly infected with HCV to develop significant neuropathological dysfunction. Further, with the exception of a single neuropsychological measure (Trails B), performance on neuropsychological tests was similar between individuals with and without evidence of HCV in the brain.
A number of other studies have demonstrated significant neuropsychological impairment among individuals infected with HCV alone. Interestingly, these studies have revealed significant cognitive compromise in the absence of either substance abuse or cirrhosis, suggesting a possible direct impact of HCV on the brain. Interested readers are referred to Perry et al. (2008)
for a recent review though we provide a brief review in this section. Hilsabeck et al. (2002
) have reported significant impairments among HCV mono-infected patients on tests of psychomotor speed, sustained attention, and working memory with impairment rates (defined as performance more than one standard deviation below that of controls) exceeding 80% on some measures. Neuropsychological performances were generally more impaired among individuals with greater liver damage but individuals with only mild liver compromise also demonstrated impaired neuropsychological functions.
Similar results were reported by Fontana et al. (2005)
using data obtained from a large clinical trial for the treatment of HCV (the HALT-C trial). In this study, more than one third of the sample met criteria for neuropsychological impairment as defined by performances at least one standard deviation below that of controls on at least four neuropsychological tests. Verbal memory and working memory were most likely impaired in this cohort and no significant correlations were observed between performances in these domains and liver severity. Most recently, Huckans et al. (2009)
examined neuropsychological function among HCV mono-infected patients with and without histories of substance abuse compared to healthy controls with no HCV and no substance abuse history. Collectively individuals with HCV performed significantly more poorly than individuals without HCV on tests of verbal memory, attention, processing speed and mental flexibility. Further, HCV mono-infected individuals without substance abuse histories performed significantly more poorly than healthy controls most of the same cognitive measures.
The studies above demonstrate that HCV mono-infection is associated with significant impairment in neuropsychological domains typically characterized as “subcortical” in nature, with predominant impact on attention, information processing speed, and verbal memory. Further, evidence of neuropsychological impairment among HCV mono-infected individuals exists independent of comorbid substance abuse and severe liver disease, raising the possibility of direct brain involvement from HCV.