It's a blood borne pathogen. Where there's blood there will also be HCV. Nice to know I don't have alzheimer's though. Sorry for the sarcasm. I'm having one of my days. Anne
From: claudine intexas <claudineintexas@...
Sent: Nov 9, 2005 11:18 PM
, Web Warriors <HepCWebWarriors@yahoogroups.com
Subject: [GIWorld-Hepatitis] HCV Found in Autopsy Brain Tissue
HCV Found in Autopsy Brain Tissue-
Emerging evidence of hepatitis C virus neuroinvasion
AIDS: Volume 19 Suppl 3 October 2005 p S140-S144
Laskus, Tomasza,c; Radkowski, Mareka,b; Adair, Debra Ma; Wilkinson, Jeffreya; Scheck, Adrienne Cc; Rakela, Jorgea
>From the aDepartment of Medicine, Mayo Clinic Scottsdale, Scottsdale, Arizona 85259
bInstitute of Infectious Diseases, Warsaw Medical Academy, Poland
cBarrow Neurological Institute, Phoenix, Arizona.
It has been reported that hepatitis C virus (HCV) infection is associated with cognitive dysfunction, fatigue and depression, which do not correlate with the severity of liver disease and cannot be accounted for by hepatic encephalopathy or drug abuse. There is also emerging evidence that HCV infection can have negative neurocognitive effects in HIV-infected cohorts. Magnetic resonance spectroscopy has suggested the likely existence of a biological basis for these effects. HCV replicative forms have recently been detected in autopsy brain tissue and the infected cells have been identified as CD68-positive (macrophages/microglia). These findings raise the possibility that HCV infection of the brain could be directly related to the reported neuropsychological and cognitive changes. HCV is not strictly hepatotropic, as it can also replicate in leukocytes, including monocytes/macrophages. The latter cells could provide access of HCV into the central nervous system ('Trojan horse'
mechanism) in a process similar to that postulated for HIV-1. In support of this hypothetical mechanism come reports showing a close relationship between HCV sequences present in the brain and cerebrospinal fluid and sequences found in lymph nodes and peripheral blood mononuclear cells. However, despite some similarities there is a fundamental difference between HIV-1 and HCV infection as the latter does not progress into AIDS-type dementia.
Hepatitis C virus (HCV) is an important etiological factor of chronic hepatitis, cirrhosis, and hepatocellular carcinoma [1,2]. The prevalence of chronic HCV infection ranges between 0.3 and 4% for most parts of the world , whereas the prevalence of antibodies to HCV in the United States is 1.8%, and approximately 2.7 million Americans carry the virus .
Hepatitis C virus infection in HIV-1-positive patients
HCV infection is common among HIV-positive patients as both pathogens share similar routes of transmission. In the United States and Europe, 13-43% of HIV-infected individuals are also infected with HCV . Moreover, HIV co-infection may facilitate mother-to-infant  and horizontal  transmission of HCV. It has been reported that HIV accelerates the development of severe liver disease in HCV-infected patients [8,9], and a recent reduction in mortality and morbidity among HIV-infected patients could have contributed to the emergence of HCV as a significant pathogen in this population. These negative effects of HIV on liver disease could be a result of the enhancement of HCV replication in the setting of immunodeficiency. However, there is also evidence that HCV replication may be directly enhanced by the presence of HIV, as HIV seroconversion in HCV-positive patients was associated with an immediate increase in serum HCV-RNA levels .
HCV infection may also negatively affect the course of HIV disease. In particular, a report from the Swiss cohort study , which included over 2000 subjects, demonstrated that HIV/HCV-co-infected patients were more likely to develop AIDS-defining opportunistic infections than those only infected with HIV. Similar findings were reported in a large Italian study  and from The Women's Interagency HIV-1 Study . However, Sulkowski et al.  did not find evidence that HCV infection substantially alters the risk of dying, developing AIDS, or responding immunologically to highly active antiretroviral therapy. These discrepancies are difficult to sort out, particularly as the cohorts and their respective controls varied in demographics and epidemiological background.
Extrahepatic replication of hepatitis C virus
HCV is not strictly hepatotropic, as it can also replicate in peripheral blood mononuclear cells (PBMC). Several groups of researchers have detected HCV-RNA negative strand, which is a viral replicative intermediate, within PBMC, and it was also demonstrated that viral genomic sequences present in PBMC are often different from those found in serum and the liver [15-18]. HCV RNA has also been detected in PBMC and hematopoietic progenitor cells by in situ hybridization . Furthermore, the same minor quasispecies variants of strain H77, which were selected in lymphoblastoid cells in vitro, were found to be replicating in vivo in PBMC of chimpanzees inoculated with the same parent strain . Within the population of PBMC, the cells harboring replicating virus have been identified primary as monocytes/macrophages and B cells, although T cells can also be infected, particularly in long-lasting infection [21-23]. The above cells may manifest functional changes in chronic hepatitis C
patients, although it is unclear whether this is directly caused by HCV infection. B-cell dysfunction is thus characterized by low-titer and delayed onset antibody response and an increased frequency of naive B cells [24,25], whereas monocyte-derived dendritic cells demonstrate impaired allostimulatory function [21,26]. It was recently shown that primary human macrophages can be infected by HCV in vitro, as evidenced by the detection of viral replicative forms, an occasional evolution of viral sequences during cell culture, and positive staining of infected cells for viral non-structural protein 3 (NS3) [27,28]. Moreover, HCV infection of macrophages in vitro may induce TNF-Î± and IL-8 .
Interestingly, there is emerging evidence that HIV could facilitate HCV replication not only in the liver, but also at extrahepatic sites [22,28]. The mechanisms by which HIV could enhance extrahepatic HCV infection are still speculative, one possibility being that this effect is related to general immunosuppression. Accordingly, in one small study viral negative strand was more common in PBMC from patients after liver transplantation than in patients before liver transplantation , and the presence of HCV replication was documented in hematopoietic cells inoculated into severe combined immunodeficiency mice . An increase in extrahepatic HCV replication could also be related to HIV-induced cell activation. In support of such a possibility come observations that the addition of pokeweed and phytohemagglutinin mitogens to PBMC cultures may significantly enhance HCV replication [22,32]. However, HIV infection could also facilitate extrahepatic replication of HCV more directly.
For example, the HIV tat protein is a strong transactivator, and a putative tat-binding motif was found in the NS4 region of HCV . We have recently shown that the same cell could harbor both pathogens, which could facilitate close viral-viral interactions .
Interestingly, in a recent study encompassing 75 HCV-infected women, 62 of whom were co-infected with HIV-1, local HIV viremia and the presence of HCV RNA in serum were the only independent predictors of HCV RNA in genital tract secretions. Significant (> 600 IU/ml) HCV viremia in cervical lavage samples was present in 28% of HIV-co-infected women and in none of the HIV-negative women . Local interactions and possible co-infection of the same cells could perhaps explain the co-transmission of HIV with HCV reported in earlier mother-to-child transmission studies conducted before the introduction of highly active antiretroviral therapy . The co-transmission of both pathogens was also reported in sexual partners of HIV/HCV-co-infected hemophiliac individuals . Extrahepatic sites of HCV replication may play a major role in viral persistence: it was recently demonstrated that the virus may linger for years at extrahepatic sites after ostensible successful treatment-induced or
spontaneous clearance [32,36]. Furthermore, extrahepatic variants were demonstrated to have a low rate of non-synonymous mutations in the hypervariable envelope region, which may suggest low immunological pressure or low replication turnover, both of which could be conducive to viral persistence .
Hepatitis C virus effect on central nervous system
There is growing evidence that patients with chronic hepatitis C are more likely to have significant changes in their physical and mental wellbeing, such as fatigue and depression, than patients with liver disease of other etiology [37,38]. These symptoms are unrelated to the mode of acquisition of the infection or to the severity of liver disease but often remit after antiviral therapy [37,39]. Two recently published studies have shown that HCV infection is associated with cognitive dysfunction [40,41]. Forton et al.  found that patients with chronic hepatitis C were impaired on cognitive tasks. Moreover, impairments in power of concentration and speed of working memory were independent of a history of injection drug use, depression or fatigue. The same researchers used proton magnetic resonance spectroscopy and demonstrated elevations in basal ganglia and white matter of choline/creatine ratios in patients with mild hepatitis C, which were not present either in healthy
volunteers or patients with hepatitis B [40,42]. These changes were unrelated to either hepatic encephalopathy or a history of injection drug use, and were more pronounced in patients with cognitive impairment. It is of note that similar proton magnetic resonance spectroscopy abnormalities were found in patients with HIV infection, which suggests some similarities between both pathogens with respect to central nervous system (CNS) involvement [43,44]. Findings suggestive of neurocognitive impairment were also reported by Kramer et al. , who used P300 event-related potentials in a large cohort of patients with chronic HCV infection. HCV infection was also associated with reduced white matter N-acetyl aspartate in abstinent methamphetamine users, suggesting that the infection may worsen methamphetamine-associated neuronal injury . Additional evidence of a likely biological basis of cognitive dysfunction is provided by a recent report showing multiple gene _expression
differences in brain tissue between HCV-positive and HCV-negative patients .
Some studies have indicated an impact of HCV on CNS function among HIV-infected cohorts. In one small sample, co-infected patients were more likely to show overall cognitive impairment than patients with exclusive HIV infection . Distinct negative neurocognitive effects of HCV co-infection were recently documented in an advanced HIV cohort . The latter two studies point to the necessity of future studies in HIV/HCV-co-infected patients, in whom cognitive impairment is generally attributed only to HIV infection.
Results of the above studies raise the possibility of direct HCV infection of the CNS. HCV belongs to the flaviviridae family, which includes well-known neurotropic viruses (e.g. yellow fever, dengue, tick-borne encephalitis viruses), and several reports have implicated HCV as an occasional cause of CNS and peripheral nervous system pathologies [50-52]. Viral sequences were also amplified directly from brain tissue from a patient diagnosed with progressive encephalomyelitis . However, the presence of viral sequences in brain tissue could be the result of blood contamination and cannot be regarded as evidence of local HCV replication. In a recent study, we detected negative-strand HCV RNA, which is a viral replicative intermediary, in autopsy brain tissue of three out of six HCV-infected patients, and in two of these patients there was evidence of viral brain compartmentalization as viral sequences amplified from the brain differed from those circulating in serum. Importantly,
brain-derived HCV variants were found to be more closely related to the virus present in the lymphoid system than to the virus circulating in serum, as based on sequence analysis of two different viral regions . A close relationship between the HCV variants present in brain tissue and those present in lymph nodes was recently reported by another group of researchers . Moreover, CNS-derived 5â²-untranslated region sequences were reported to have reduced translation efficiency compared with virus present in the serum and liver. The latter finding is compatible with a slow replication rate of brain HCV strains and could perhaps favor viral latency.
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-Î±, 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 .
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