Peculiarities of the Expression of Immunohistochemical Marker HCV nS3 in the Autopsy Brain of the Patients Died in the Outcome of Chronic Infection, Caused by Hepatitis C Virus

Background. Brain lesion is one of the most common extrahepatic manifestations of chronic HCV infection. To date, its main clinical and neurometabolic features have been established. However, the morphological picture of HCV-associated cerebral changes and peculiarities of viral molecular markers expression in brain matter remain poorly understood. This significantly limits the possibilities of pathological diagnosis of this disease.

Aims. To study the morphological picture of brain lesion during chronic HCV infection and to determine the peculiarities of immunohistochemical (IHC) expression of the HCV NS3 antigen in brain matter.

Materials and methods. The study was performed on autopsy brain of 40 patients who died in the outcome of HCV infection and 15 patients died without signs of mental pathology. Complex of pathomorphological and ICH methods was used.

Results. It was demonstrated that morphological picture of brain lesion in chronic HCV infection is represented by nonspecific dystrophic, inflammatory and proliferative changes, the severity of which varies significantly depending on the brain departments (p < 0.001). Expression of the NS3 marker is found in all studied brain regions and shows the highest intensity in white matter of cerebral hemispheres and in brain stem (p < 0.05). The ICH reaction of NS3 is manifested in microglia cells, vascular endothelium, inflammatory infiltrate cells and in periventricular ependyma cells. Using correlation analysis method it was found that NS3 expression formed the strongest correlations with such categories as CD68 expression, microgliosis, and axonal degeneration. This allows considering they are the main factors by which HCV realizes its deleterious effect on the brain.

Conclusion. Characteristic morphological changes of the brain in chronic HCV infection were studied. The features of ICH expression of the NS3 in various parts of the brain are established. The results can be used to improve pathological diagnosis of brain lesion in chronic HCV infection.

1. Tsinzerling VA, Chuhlovina ML. Infectious lesions of nervous system: etiology, pathogenesis and diagnostics: guidelines for specialists. Saint-Petersburg: ELBI-SPb; 2011. (In Russ.)

2. Lingala S, Ghany MG. Natural history of Hepatitis C. Gastroenterol Clin North Am. 2015; 44(4): 717-734. doi: 10.1016/j.gtc.2015.07.003

3. Mathew S, Faheem M, Ibrahim SM, Iqbal W, Rauff B, Fatima K, et al. Hepatitis C virus and neurological damage. World J Hepatol. 2016; 8(12): 545-556. doi: 10.4254/wjh.v8.i12.545

4. Yarlott L. Heald E, Forton D. Hepatitis C virus infection, and neurological and psychiatric disorders - a review. J Adv Res. 2017; 8(2): 139-148. doi: 10.1016/j.jare.2016.09.005

5. Hilsabeck RC, Hassanein TI, Carlson MD, Ziegler EA, Perry W. Cognitive functioning and psychiatric symptomatology in patients with chronic hepatitis C. J Int Neuropsychol Soc. 2003; 9(6): 847-857. doi: 10.1017/S1355617703960048

6. Weissenborn K, Ennen JC, Bokemeyer M, Ahl B, Wurster U, Tillmann H, et al. Monoaminergic neurotransmission is altered in hepatitis C virus infected patients with chronic fatigue and cognitive impairment. Gut. 2006; 55(11): 1624-1630. doi: 10.1136/gut.2005.080267

7. 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(2): 433439. doi: 10.1053/jhep.2002.30688

8. 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(4): 305-308. doi: 10.1016/0303-8467(96)00040-6

9. Seifert F, Struffert T, Hildebrandt M, Blumcke I, Bruck W, Staykov D, et al. In vivo detection of hepatitis C virus (HCV) RNA in the brain in a case of encephalitis: evidence for HCV neuroinvasion. Eur J Neurol. 2008; 15(3): 214-218. doi: 10.1111/j.1468-1331.2007.02044.x

10. 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(10): 5170-5183. doi: 10.1128/jvi.78.10.5170-5183.2004

11. 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(2): 600-608. doi: 10.1128/jvi.76.2.600-608.2002

12. Wilkinson J, Radkowski M, Laskus T. Hepatitis C Virus neuroinvasion: identification of infected cells. J Virol. 2009; 83(3): 1312-1319. doi: 10.1128/JVI.01890-08

13. Fletcher NF, Wilson GK, Murray J, Hu K, Lewis A, Reynolds GM, et al. Hepatitis C virus infects the endothelial cells of the blood-brain barrier. Gastroenterology. 2012; 142(3): 634-643. e6. doi: 10.1053/j.gastro.2011.11.028

14. Bokemeyer M, Ding XQ, Goldbecker A, Raab P, Heeren M, Arvanitis D, et al. Evidence for neuroinflammation and neuroprotection in HCV infection-associated encephalopathy. Gut. 2011; 60(3): 370-377. doi: 10.1136/gut.2010.217976

15. Pawlowski T, Radkowski M, Malyszczak K, Inglot M, Zalewska M, Jablonska J, et al. Depression and neuroticism in patients with chronic hepatitis C: correlation with peripheral blood mononuclear cells activation. J Clin Virol. 2014; 60(2): 105-111. doi: 10.1016/j.jcv.2014.03.004

16. Grover VP, Pavese N, Koh SB, Wylezinska M, Saxby BK, Gerhard A, et al. Cerebral microglial activation in patients with hepatitis C: in vivo evidence of neuroinflammation. J Viral Hepat. 2012; 19(12): e89-96. doi: 10.1111/j.1365-2893.2011.01510.x

17. Forton DM, Hamilton G, Allsop JM, Grover VP, Wesnes K, O'Sullivan C, et al. Cerebral immune activation in chronic hepatitis C infection: а magnetic resonance spectroscopy study. J Hepatol. 2008; 49(3): 316-322. doi: 10.1016/j.jhep.2008.03.022

18. Tchubinidze AI. On the methodology of histological (morphological) determination of the degree of damage to the central nervous system. Archive pathologii. 1972; 34(11): 77-78. (In Russ.)

19. Herder V, Hansmann F, Wohlsein P, Peters M, Varela M, Palmarini M, et al. Immunophenotyping of inflammatory cells associated with Schmallenberg virus infection of the central nervous system of ruminants. PLoS One. 2013; 8(5): e62939. doi: 10.1371/journal.pone.0062939

20. Younis LK, Talaat FM, Deif AH, Borei MF, Reheim SM, El Salmawy DH. Immunohistochemical detection of HCV in nerves and muscles of patients with HCV associated peripheral neuropathy and myositis. Int J Health Sci (Qassim). 2007; 1(2): 195-202.

21. Maybogin AM, Nedzved MK, Karapetyan GM. Method for the morphological diagnosis of microgliosis in the white matter of the brain (instructions for use). Gomel, Republic of Belarus: Gomel State Medical University; 2014. (In Russ.)

22. Maybogin AM, Nedzvedz MK. Microgliosis in white matter of the brain in chronic HCV-infection: morphological study. HIV Infection and Immunosuppresive Disorders. 2019; 11(3): 49-56. (In Russ.)