|
|
||||
|
|
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
Institute of Infectious Diseases, Warsaw Medical Academy, Poland cBarrow Neurological Institute, Phoenix, Arizona.
Abstract
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.
Introduction
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 [3], whereas the prevalence of
antibodies to HCV in the United States is 1.8%, and approximately
2.7 million Americans carry the virus [4].
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 [5]. Moreover, HIV co-infection may facilitate
mother-to-infant [6] and horizontal [7] 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 [10].
HCV infection may also negatively affect the course of HIV disease.
In particular, a report from the Swiss cohort study [11], 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 [12] and from The Women's
Interagency HIV-1 Study [13]. However, Sulkowski et al. [14] 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 [19]. 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 [20]. 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-α and
IL-8 [29].
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 [30], and the presence of HCV
replication was documented in hematopoietic cells inoculated into
severe combined immunodeficiency mice [31]. 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 [33]. We have recently shown that the
same cell could harbor both pathogens, which could facilitate close
viral-viral interactions [28].
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 [34].
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 [35]. The
co-transmission of both pathogens was also reported in sexual
partners of HIV/HCV-co-infected hemophiliac individuals [7].
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 [23].
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. [40]
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. [45], 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 [46]. 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 [47].
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 [48]. Distinct negative neurocognitive
effects of HCV co-infection were recently documented in an advanced
HIV cohort [49]. 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 [50]. 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 [53]. 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 [54].
Moreover, CNS-derived 5′-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 [47]. 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 [55]. 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 [62], 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 [23].
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 [65]. 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 [28].
References 1. Alter MJ, Margolis HS, Krawczynski K, Judson FN, Mares A, Alexander WJ, et al. The natural history of community-acquired hepatitis C in the United States. The Sentinel Counties Chronic non-A, non-B Hepatitis Study Team. N Engl J Med 1992; 327:1899-1905. 2. Simonetti RG, Camma C, Fiorello F, Cottone M, Rapicetta M, Marino L, et al. Hepatitis C virus infection as a risk factor for hepatocellular carcinoma in patients with cirrhosis. A case-control study. Ann Intern Med 1992; 116:97-102. 3. Nishioka K. Epidemiological studies on hepatitis C virus infection: detection, prevalence, exposure and prevention. Intervirology 1994; 37:58-67. 4. Alter MJ, Kruszon-Moran D, Nainan OV, McQuillan GM, Gao F, Moyer LA, et al. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med 1999; 341:556-562. 5. Winnock M, Salmon-Ceron D, Dabis F, Chene G. Interaction between HIV-1 and HCV infections: towards a new entity? J Antimicrob Chemother 2004; 53:936-946. 6. Zanetti AR, Tanzi E, Paccagnini S, Principi N, Pizzocolo G, Caccamo ML, et al. Mother-to-infant transmission of hepatitis C virus. Lombardy Study Group on Vertical HCV Transmission [see Comments]. Lancet 1995; 345:289-291. 7. Eyster ME, Alter HJ, Aledort LM, Quan S, Hatzakis A, Goedert JJ. Heterosexual co-transmission of hepatitis C virus (HCV) and human immunodeficiency virus (HIV). Ann Intern Med 1991; 115:764-768. 8. Eyster ME, Diamondstone LS, Lien JM, Ehmann WC, Quan S, Goedert JJ. Natural history of hepatitis C virus infection in multitransfused hemophiliacs: effect of coinfection with human immunodeficiency virus. The Multicenter Hemophilia Cohort Study. J Acquir Immune Defic Syndr 1993; 6:602-610. 9. Hanley JP, Jarvis LM, Andrews J, Dennis R, Lee R, Simmonds P, et al. Investigation of chronic hepatitis C infection in individuals with haemophilia: assessment of invasive and non-invasive methods. Br J Haematol 1996; 94:159-165. 10. Beld M, Penning M, Lukashov V, McMorrow M, Roos M, Pakker N, et al. Evidence that both HIV and HIV-induced immunodeficiency enhance HCV replication among HCV seroconverters. Virology 1998; 244:504-512. 11. Greub G, Ledergerber B, Battegay M, Grob P, Perrin L, Furrer H, et al. Clinical progression, survival, and immune recovery during antiretroviral therapy in patients with HIV-1 and hepatitis C virus coinfection: the Swiss HIV Cohort Study. Lancet 2000; 356:1800-1805. 12. De Luca A, Bugarini R, Lepri AC, Puoti M, Girardi E, Antinori A, et al. Coinfection with hepatitis viruses and outcome of initial antiretroviral regimens in previously naive HIV-infected subjects. Arch Intern Med 2002; 162:2125-2132. 13. Kovacs A, Du W, DeGiacomo M, Shahidyazdani T, Wright D, Nowicki J. Impact of HCV viremia on HIV disease progression in women. In: 15th International AIDS Conference. Bangkok, Thailand, 11-16 July 2004 [Abstract MoPeB3343]. 14. Sulkowski MS, Moore RD, Mehta SH, Chaisson RE, Thomas DL. Hepatitis C and progression of HIV disease. JAMA 2002; 288:199-206. 15. Laskus T, Radkowski M, Wang LF, Jang SJ, Vargas H, Rakela J. Hepatitis C virus quasispecies in patients infected with HIV-1: correlation with extrahepatic viral replication. Virology 1998; 248:164-171. 16. Laskus T, Radkowski M, Wang LF, Nowicki M, Rakela J. Uneven distribution of hepatitis C virus quasispecies in tissues from subjects with end-stage liver disease: confounding effect of viral adsorption and mounting evidence for the presence of low-level extrahepatic replication. J Virol 2000; 74:1014-1017. 17. Lerat H, Rumin S, Habersetzer F, Berby F, Trabaud MA, Trépo C, et al. In vivo tropism of hepatitis C virus genomic sequences in hematopoietic cells: influence of viral load, viral genotype, and cell phenotype. Blood 1998; 91:3841-3849. 18. Navas S, Martin J, Quiroga JA, Castillo I, Carreno V. Genetic diversity and tissue compartmentalization of the hepatitis C virus genome in blood mononuclear cells, liver, and serum from chronic hepatitis C patients. J Virol 1998; 72:1640-1646. 19. Sansonno D, Iacobelli AR, Cornacchiulo V, Iodice G, Dammacco F. Detection of hepatitis C virus (HCV) proteins by immunofluorescence and HCV RNA genomic sequences by non-isotopic in situ hybridization in bone marrow and peripheral blood mononuclear cells of chronically HCV- infected patients. Clin Exp Immunol 1996; 103:414-421. 20. Shimizu YK, Igarashi H, Kanematu T, Fujiwara K, Wong DC, Purcell RH, et al. Sequence analysis of the hepatitis C virus genome recovered from serum, liver, and peripheral blood mononuclear cells of infected chimpanzees. J Virol 1997; 71:5769-5773. 21. Bain C, Fatmi A, Zoulim F, Zarski JP, Trepo C, Inchauspe G. Impaired allostimulatory function of dendritic cells in chronic hepatitis C infection. Gastroenterology 2001; 120:512-524. 22. Laskus T, Radkowski M, Piasek A, Nowicki M, Horban A, Cianciara J, et al. Hepatitis C virus in lymphoid cells of patients coinfected with human immunodeficiency virus type 1: evidence of active replication in monocytes/macrophages and lymphocytes. J Infect Dis 2000; 181:442-448. 23. Ducoulombier D, Roque-Afonso AM, Di Liberto G, Penin F, Kara F, Richard Y, et al. Frequent compartmentalization of hepatitis C virus variants in circulating B cells and monocytes. Hepatology 2004; 39:817-825. 24. Chen M, Sallberg M, Sönnerborg A, Weiland O, Mattsson L, Jin L, et al. Limited humoral immunity in hepatitis C virus infection. Gastroenterology 1999; 116:135-143. 25. Ni J, Hembrador E, Di Bisceglie AM, Jacobson IM, Talal AH, Butera D, et al. Accumulation of B lymphocytes with a naive, resting phenotype in a subset of hepatitis C patients. J Immunol 2003; 170:3429-3439. 26. Auffermann-Gretzinger S, Keeffe EB, Levy S. Impaired dendritic cell maturation in patients with chronic, but not resolved, hepatitis C virus infection. Blood 2001; 97:3171-3176. 27. Caussin-Schwemling C, Schmitt C, Stoll-Keller F. Study of the infection of human blood derived monocyte/macrophages with hepatitis C virus in vitro. J Med Virol 2001; 65:14-22. 28. Laskus T, Radkowski M, Jablonska J, Kibler K, Wilkinson J, Adair D, et al. Human immunodeficiency virus facilitates infection/replication of hepatitis C virus in native human macrophages. Blood 2004; 103:3854-3859. 29. Radkowski M, Bednarska A, Horban A, Stanczak J, Wilkinson J, Adair DM, et al. Infection of primary human macrophages with hepatitis C virus in vitro: induction of tumour necrosis factor-alpha and interleukin 8. J Gen Virol 2004; 85:47-59. 30. Radkowski M, Wang LF, Vargas HE, Rakela J, Laskus T. Detection of hepatitis C virus replication in peripheral blood mononuclear cells after orthotopic liver transplantation. Transplantation 1998; 66:664-666. 31. Bronowicki JP, Loriot MA, Thiers V, Grignon Y, Zignego AL, Brechot C. Hepatitis C virus persistence in human hematopoietic cells injected into SCID mice. Hepatology 1998; 28:211-218. 32. Pham TN, MacParland SA, Mulrooney PM, Cooksley H, Naoumov NV, Michalak TI. Hepatitis C virus persistence after spontaneous or treatment-induced resolution of hepatitis C. J Virol 2004; 78:5867-5874. 33. Ferbeyre G, Bourdeau V, Cedergren R. Does HIV tat protein also regulate genes of other viruses present in HIV infection? [Letter]. Trends Biochem Sci 1997; 22:115-116. 34. Rakela J, Radkowski M, Laskus T, Wilkinson J, Adair D, Kovacs A, et al. HCV presence in genital secretions in HIV/HCV coinfected women. Hepatology 2003; 38:184A. 35. Papaevangelou V, Pollack H, Rochford G, Kokka R, Hou Z, Chernoff D, et al. Increased transmission of vertical hepatitis C virus (HCV) infection to human immunodeficiency virus (HIV)-infected infants of HIV- and HCV-coinfected women. J Infect Dis 1998; 178:1047-1052. 36. Radkowski M, Gallegos-Orozco JF, Jablonska J, Colby TF, Walewska-Zielecka B, Kubicka J, et al. Persistence of hepatitis C virus in patients successfully treated for chronic hepatitis C. Hepatology 2004; 41:106-114. 37. Foster GR. Hepatitis C virus infection: quality of life and side effects of treatment. J Hepatol 1999; 31:250-254. 38. Singh N, Gayowski T, Wagener MM, Marino IR. Quality of life, functional status, and depression in male liver transplant recipients with recurrent viral hepatitis C. Transplantation 1999; 67:69-72. 39. Bonkovsky HL, Woolley JM. Reduction of health-related quality of life in chronic hepatitis C and improvement with interferon therapy. The Consensus Interferon Study Group [see Comments]. Hepatology 1999; 29:264-270. 40. Forton DM, Thomas HC, Murphy CA, Allsop JM, Foster GR, Main J, et al. Hepatitis C and cognitive impairment in a cohort of patients with mild liver disease. Hepatology 2002; 35:433-439. [Medline Link] [CrossRef] [Context Link] 41. Hilsabeck RC, Perry W, Hassanein TI. Neuropsychological impairment in patients with chronic hepatitis C. Hepatology 2002; 35:440-446. 42. Forton DM, Allsop JM, Main J, Foster GR, Thomas HC, Taylor-Robinson SD. Evidence for a cerebral effect of the hepatitis C virus. Lancet 2001; 358:38-39. 43. Marcus CD, Taylor-Robinson SD, Sargentoni J, Ainsworth JG, Frize G, Easterbrook PJ, et al. 1H MR spectroscopy of the brain in HIV-1-seropositive subjects: evidence for diffuse metabolic abnormalities. Metab Brain Dis 1998; 13:123-136. 44. Meyerhoff DJ, Bloomer C, Cardenas V, Norman D, Weiner MW, Fein G. Elevated subcortical choline metabolites in cognitively and clinically asymptomatic HIV+ patients. Neurology 1999; 52:995-1003. 45. Kramer L, Bauer E, Funk G, Hofer H, Jessner W, Steindl-Munda P, et al. Subclinical impairment of brain function in chronic hepatitis C infection. J Hepatol 2002; 37:349-354. 46. Taylor MJ, Letendre SL, Schweinsburg BC, Alhassoon OM, Brown GG, Gongvatana A, et al. Hepatitis C virus infection is associated with reduced white matter N-acetylaspartate in abstinent methamphetamine users. J Int Neuropsychol Soc 2004; 10:110-113. 47. Adair D, Wilkinson J, Scheck A, Radkowski M, Rakela J, Laskus T. Differential display and microarray analysis show differentially expressed genes in central nervous system in HCV infected patients and laser capture microscopy points to brain microglia as cells harboring HCV. Hepatology 2004; 40:433A. 48. Letendre SL, Cherner M, Ellis R, Grant I. Individuals coinfected with hepatitis C (HCV) and HIV are more cognitively impaired than those infected with either virus alone [Abstract]. J Neurovirol 2002; 8:27-28. 49. Ryan EL, Morgello S, Isaacs K, Naseer M, Gerits P. Neuropsychiatric impact of hepatitis C on advanced HIV. Neurology 2004; 62:957-962. 50. Bolay H, Soylemezoglu F, Nurlu G, Tuncer S, Varli K. PCR detected hepatitis C virus genome in the brain of a case with progressive encephalomyelitis with rigidity. Clin Neurol Neurosurg 1996; 98:305-308. 51. Heckmann JG, Kayser C, Heuss D, Manger B, Blum HE, Neundorfer B. Neurological manifestations of chronic hepatitis C. J Neurol 1999; 246:486-491. 52. Origgi L, Vanoli M, Carbone A, Grasso M, Scorza R. Central nervous system involvement in patients with HCV-related cryoglobulinemia. Am J Med Sci 1998; 315:208-210. 53. Radkowski M, Wilkinson J, Nowicki M, Adair D, Vargas H, Ingui C, et al. Search for hepatitis C virus negative-strand RNA sequences and analysis of viral sequences in the central nervous system: evidence of replication. J Virol 2002; 76:600-608. 54. Forton DM, Karayiannis P, Mahmud N, Taylor-Robinson SD, Thomas HC. Identification of unique hepatitis C virus quasispecies in the central nervous system and comparative analysis of internal translational efficiency of brain, liver, and serum variants. J Virol 2004; 78:5170-5183. 55. Hickey WF. Leukocyte traffic in the central nervous system: the participants and their roles. Semin Immunol 1999; 11:125-137. 56. Hickey WF, Vass K, Lassmann H. Bone marrow-derived elements in the central nervous system: an immunohistochemical and ultrastructural survey of rat chimeras. J Neuropathol Exp Neurol 1992; 51:246-256. 57. Unger ER, Sung JH, Manivel JC, Chenggis ML, Blazar BR, Krivit W. Male donor-derived cells in the brains of female sex-mismatched bone marrow transplant recipients: a Y-chromosome specific in situ hybridization study. J Neuropathol Exp Neurol 1993; 52:460-470. 58. Hickey WF, Hsu BL, Kimura H. T-lymphocyte entry into the central nervous system. J Neurosci Res 1991; 28:254-260. 59. Knopf PM, Harling-Berg CJ, Cserr HF, Basu D, Sirulnick EJ, Nolan SC, et al. Antigen-dependent intrathecal antibody synthesis in the normal rat brain: tissue entry and local retention of antigen-specific B cells. J Immunol 1998; 161:692-701. 60. Maggi F, Giorgi M, Fornai C, Morrica A, Vatteroni ML, Pistello M, et al. Detection and quasispecies analysis of hepatitis C virus in the cerebrospinal fluid of infected patients. J Neurovirol 1999; 5:319-323. 61. Morsica G, Bernardi MT, Novati R, Uberti Foppa C, Castagna A, Lazzarin A. Detection of hepatitis C virus genomic sequences in the cerebrospinal fluid of HIV-infected patients. J Med Virol 1997; 53:252-254. 62. Laskus T, Radkowski M, Bednarska A, Wilkinson J, Adair D, Nowicki M, et al. Detection and analysis of hepatitis C virus sequences in cerebrospinal fluid. J Virol 2002; 76:10064-10068. 63. Price RW, Sidtis J, Rosenblum M. The AIDS dementia complex: some current questions. Ann Neurol 1988; 23(Suppl.):S27-S33. 64. Zheng J, Gendelman HE. The HIV-1 associated dementia complex: a metabolic encephalopathy fueled by viral replication in mononuclear phagocytes. Curr Opin Neurol 1997; 10:319-325. 65. Davis EJ, Foster TD, Thomas WE. Cellular forms and functions of brain microglia. Brain Res Bull 1994; 34:73-78. 66. Capuron L, Dantzer R. Cytokines and depression: the need for a new paradigm. Brain Behav Immun 2003; 17(Suppl. 1):S119-S124. [Medline Link] [Context Link] 67. Wilson CJ, Finch CE, Cohen HJ. Cytokines and cognition - the case for a head-to-toe inflammatory paradigm. J Am Geriatr Soc 2002; 50:2041-2056. 68. Kolson DL, Lavi E, Gonzalez-Scarano F. The effects of human immunodeficiency virus in the central nervous system. Adv Virus Res 1998; 50:1-47. 69. Pulliam L, Herndier BG, Tang NM, McGrath MS. Human immunodeficiency virus-infected macrophages produce soluble factors that cause histological and neurochemical alterations in cultured human brains. J Clin Invest 1991; 87:503-512. Psychiatric Disorders Common Among HCV-Infected Veterans NEW YORK (Reuters Health) Aug 29 - 2002 Psychiatric disorders and problems
with drug or alcohol use are more common among military veterans who are
infected with hepatitis C virus (HCV) than among veterans who are not,
according to a report published in the August issue of Gastroenterology.
Note: Finally it is documented, HCV
veterans are experiencing opportunist psychiatric illnesses as a result of
Hepatitis C. We have know for years most vets with HCV have an array of
psychiatric conditions. The most common among Vietnam veterans is PTSD.
Hepatitis C and
the Brain These investigators found an association with HCV-RNA positivity in
the cerebrospinal fluid of HCV-infected persons, particularly in
association with the cellular compartment. The presence of the negative
strand of HCV suggested active HCV replication rather than contamination
from the peripheral blood. In patients harboring different strains of HCV
in serum and peripheral blood mononuclear cells (PBMCs), as determined by
phylogenetic analysis, cerebrospinal fluid-derived strains were more
closely related to those found in PBMCs than in serum. The study authors
proposed that PBMCs could carry the virus into the central nervous system
and provide a mechanism for HCV neuroinvasion. Ref: Cognitive Brain Function Is Subclinically Impaired In Patients With Chronic Hepatitis C - Does Hepatitis C Affect The Brain? Primary author: L. Kramer and colleagues, Department of Medicine IV, University of Vienna, Austria Author interviewed: Petra Steindl-Munda, M.D. In brief: Non-cirrhotic hepatitis C patients were found to have some subclinical impairment of cerebral function prior to combination therapy with interferon and ribavirin. After 16 weeks of therapy, one measure of cognitive function returned to normal range. Measures of health-related quality of life did not improve. Besides affecting the liver, hepatitis C is known to affect the central nervous system more frequently than other liver diseases, causing depression and fatigue. Similarly, patients with hepatitis C show greater impairment of health-related quality of life measures than do patients with hepatitis B. Because no correlation has been found between fatigue and ALT level or histological severity of hepatitis, people have hypothesized that HCV may directly affect the brain. To examine this possibility, this study aimed to determine whether hepatitis C caused measurable but subclinical cognitive impairment by using a highly sensitive, quantitative measure of brain function. It also sought to determine whether treatment with combination therapy improved cognitive function. The patient population consisted of 83 non-cirrhotic patients with chronic HCV infection treated at an Austrian hospital. Their mean age was 46 +/- 12 years (same as controls). The clinical diagnosis of HCV was made using serum HCV antibodies in an enzyme-linked immunoassay and confirmed by PCR of HCV RNA in the absence of other causes of liver disease. The study protocol involved use of the SF-36 questionnaire to measure health-related quality of life. Fatigue was quantified by validated questionnaires. Cognitive processing was measured using P300 event-related potentials, a highly sensitive and objective test of cognitive function that measures the brain's response to an acute audio stimulus. (P300 latency is a measure of processing speed. P300 amplitude reflects the amount of attention given to the stimulus.) At baseline, patients with HCV showed a slower reaction time and a lower amplitude than a control group of {number?} matched, healthy subjects. The results showed a marked prolongation in the P300 latency in hepatitis C patients of 359 milliseconds compared to 338 milliseconds for the control group. Additionally, the amplitude of response was lower in hepatitis C patients compared to the control group, as shown in the chart below.
For purposes of comparison, measures of P300 potentials of HCV patients are listed in the table below with the potentials of patients with other diseases (as measured in other experiments). The effect of HCV infection was similar to several other diseases, and latency was worse than in patients with insulin dependent diabetes. CEREBRAL DYSFUNCTION IN HCV INFECTION vs. OTHER MEDICAL CONDITIONS
In the second phase of the experiment, hepatitis patients were given a standard regimen of interferon plus ribavirin combination therapy. Twenty patients who started a 38-week course of interferon plus ribavirin combination treatment had their P300 latencies measured at week 16. In that group, the P300 latency was 349 milliseconds in that group of patients returned to normal, to 336 in the majority of patients, according to Petra Steindl-Munda, M.D., one of the study investigators. Dr. Steindl-Munda is Professor of Medicine at the University of Vienna in Austria.The study concluded that patients with chronic hepatitis C infection exhibit a sub-clinical neurophysiological dysfunction that tended to improve with antiviral combination treatment. But according to the data analyzed to date, no clear correlation emerged between measures of hepatitis activity and neurophysiological dysfunction. Commentary The percentage of people with hepatitis C that complain about fatigue and quality of life is much higher than in other liver diseases. Dr. Steindl-Munda said. The idea was to see whether there is a correlation between this fatigue and quality of life and [histologic] activity of hepatitis to an objective measurement such as the P300. Commenting on the limitations of the study, Dr. Steindl-Munda said results were still being collected for the remaining 63 patients who are still under treatment. She noted that the majority of patients who received 16 weeks of antiviral treatment recorded a normal P300 latency of 336 [milliseconds]. This was a significant difference, she said, comparing the scores to those of HCV patients prior to treatment. More data, she noted, were also needed to see if this finding continues with the larger patient group. Additionally, the researchers will examine whether the P300 potential scores will correlate any better with quality of life measurements. The results that we have already analyzed did not reveal any correlation between quality of life, prolongation of P300, and activity of hepatitis, she said. But we will continue and see if there are any correlations that will come out. Researchers will take P300 measurements at the end of combination therapy (week 38) to compare them to week 16 results. Additionally, the study will look at whether the non-responder to treatment will return back to normal, or whether there are any changes after the end of therapy, Dr. Steindl-Munda said.Disclosure This study was independently funded without
contributions from any drug company. The authors have no relations with
Amgen Inc. We know that HIV enters the brain shortly after a person is infected with HIV. It does appear as though individuals with HIV may experience symptoms related to this, such as reduced alertness or a slower thinking capacity due to HIV. At both recent liver conferences (DDW and EASL), two different research groups reported research findings suggesting that HCV in individuals with less advanced disease (non-cirrhotics or mild fibrosis) affects the brain and reduces its functioning capacity. This suggests that a person with both HCV and HIV may be affected even more with regards to brain functioning. Over the years people with HIV have complained about experiencing fatigue and/or itching. We now know that many people with HIV also have HCV, and that HCV can cause itching and fatigue. The findings reported at DDW and EASL suggest that HCV related fatigue may be associated with the affect of HCV on the brain. It's known that individuals with advanced cirrhosis can experience hepatic encephalopothy which can cause brain disorder, but it's important to bear in mind that the participants in the studies discussed below did not have such advanced HCV disease, so the brain dysfunctioning found was not due to hepatic encephalopoathy. At EASL, DM Horton presented an oral talk on brain dysfunction in people with HCV for a UK research group from the Imperial College School of Medicine and St Mary's Hospital in London. First he reviewed two studies. He mentioned a UK study (Foster et al 1998) using the SF-36 questionnaire, and reported people with HCV compared to normal controls scored worse in physical and social functioning, energy and fatigue, and other measures. These results were independent of intravenous drug use. In a large US (Johnson et al 1998), 309 IVDUs both with or without HCV were tested for depression and those with HCV (57.2%) were found to have significantly more depressive symptomology than those who were negative to hepatitis (48.2%). In an attempt to further define this neuropsychological syndrome, they administered a battery of neuropsychometric tests to 15 patients with histologically mild hepatitis C from liver biopsy. They tested for attention (included: simple reaction time, choice reaction time), working memory (numeric & spatial working memory), and secondary memory (delayed word recall). They found that patients with mild or minimal hepatitis C from liver biopsy were slower in tests of working memory. He noted that although they were slow, their accuracy on these tasks was preserved, and this has been described in chronic fatigue syndrome. There were no attention or secondary memory abnormalities. In the view of these findings they asked themselves, if HCV infects cells in the CNS (central nervous system), does this cause cerebral metabolite abnormalities, and is cerebral HCV infection the cause of the observed neuropsychological symptoms? They carried out a proton cerebral magnetic resonance spectroscopy study to determine if metabolite abnormalities exist in the brain of patients with histologically mild hepatitis C. They randomly selected 30 patients with biopsy proven mild or minimal hepatitis due to HCV. As well, they studied 29 matched controls, and 12 eAG+ve patients with chronic HBV. No patient in the HBV or HCV groups had significant fibrosis or cirrhosis. The researchers reported seeing metabolic abnormalities in the testing in those with HCV compared to both normals (volunteers) and chronic HBV patients. There were no statistical differences between the normals and those with HBV. These abnormalities were not due to hepatic encephalopathy. They described the abnormalities as being similar to those abnormalities observed in HIV. Again, no patient in this study had significant fibrosis or cirrhosis. None of the study participants had used IV drugs in the 6 months preceding the study. There was no statistical difference in the study results between those with or without prior drug use. Those with prior drug use had the same abnormalities as those who never used IV drugs. The researchers concluded that prior drug use did not affect the outcome of the study. Is there direct infection by HCV of the
CNS? DM Horton presented a suggested potential model by which this could happen. Microglial cells in the brain turn over slowly and are replenished by
circulating monocytes, possibly up to 30% in one year. Circulating
monocytes are potentially infectable by HCV, and may carry the virus
across the blood brain barrier into the brain and the microglial cells.
Once in the cells they become activated and produce chemokines, cytokines,
and neurosteroids which may mediate the neuropsychiatric symptoms
described in this presentation. The question still remains--does HCV
infect the microglial cells in the brain? The only way to answer this
question is to conduct direct post mortem viralogic examination of brain
tissue, which is being currently undertaken at Imperial College School of
Medicine in London. He also suggested that of equal or possibly greater importance is the possibility that the brain may act as a sancutary site for HCV, allowing immune evasion and protection against antiviral therapy. He suggested that cessation of viral production from the liver may occur during phase 1 of viral decline after starting HCV therapy, but the slower viral decline during phase 2 may be due to a continued release of virus from the brain. He suggested that an alternative explanation for possible brain dysfunction seen with HCV could be that systemic cytokines cross the blood-brain barrier and may exert an effect. But he discounted this theory because in this study patients with HBV had normal spectroscopy. HCV antiviral therapy has been administered to the study patients and results are pending. In the study reported at DDW, and discussed above, the study authors reported therapy improved cerebral function, and they suggest their data may indicate a direct action of HCV infection on the brain. PSYCHOLOGIC STRESS, DEPRESSION AND QUALITY OF LIFE IN PATIENTS WITH LIVER DISEASE DUE TO HEPATITIS C VIRUS N. Singh^{*}, T. Gayowski, M.M. Wagener, I.R. Marino. Veterans Affairs Medical Center, Pittsburgh, PA. Background: Methods: Results: Conclusion: |
