Epstein-Barr Virus May Contribute to Central Nervous System Involvement in HIV-positive Individuals

Lupia, T.; Milia, M. G.; atzori, c.; Audagnotto, S.; imperiale, d.; mighetto, l.; pirriatore, v.; Gregori, G.; lipani, f.; Ghisetti, V.; Bonora, S.; Di Perri, G.; Calcagno, A.

doi:10.1101/341354

bioRxiv · 10.1101/341354

Epstein-Barr Virus May Contribute to Central Nervous System Involvement in HIV-positive Individuals

Lupia, T.·Milia, M. G.·atzori, c.·Audagnotto, S.·imperiale, d.·mighetto, l.·pirriatore, v.·Gregori, G.·lipani, f.·Ghisetti, V.·Bonora, S.·Di Perri, G.·Calcagno, A.

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Abstract

Epstein-Barr virus (EBV) often accesses the central nervous system (CNS) where it may lead to blood brain barrier (BBB) integrity disruption, facilitating the migration of immune cells into brain parenchyma. Our aim was to study the association between cerebrospinal fluid (CSF) EBV DNA and HIV-1 compartmental replication. 281 HIV-positive adults undergoing lumbar punctures for clinical reasons (excluding those with lymphoproliferative disorders) and CSF samples were examined. CSF virological, neurodamage (tau, p-tau, 1-42 beta amyloid) and immune activation (neopterin and S100beta) markers were measured by immune-enzymatic, ELISA and PCR validated methods. Two hundred eighty one patients were included; 111 (40.5 %) were naive for antiretroviral treatment. CSF EBV DNA was detectable in 25 (21.9%) naive and 26 (16%) treated patients at low levels (<100 and 146 copies/mL). Naive EBV+ subjects presented higher CSF HIV RNA, biomarkers (t-tau, p-tau, neopterin) and higher rates of pleocytosis. Treated EBV+ individuals showed pleocytosis, higher CSF HIV RNA, CSF to serum albumin ratio, IgG index and neopterin. No association was observed between detectable CSF EBV DNA and the rate of CSF escape. In patients with plasma HIV RNA <20 copies/mL (n=97) CSF EBV DNA was detectable in 13 subjects (13.4%) and it was associated with pleocytosis, higher CSF HIV RNA and neopterin levels. EBV DNA was detectable in a considerable proportion of HIV-positive patients and it was associated with higher levels of CSF HIV RNA and neuronal damage/inflammation biomarkers. The role of EBV reactivation in HIV-associated CNS disorders warrant further studies.\n\nImportanceEBV is a human gamma-herpesvirus with a seroprevalence in adults approaches 95% and the pattern of clinical manifestations is very heterogeneous and varies from asymptomatic or mild viral infection to a tightly linked with several malignancies as nasopharyngeal carcinoma, Hodgkins lymphoma and Burkitts lymphoma. HIV-infected and immunocompetent patients were both at risk of primary infection and complications linked to EBV.\n\nPrimary tropism of EBV is for lymphocytes (type B, T and NK), epithelial, endothelial and smooth muscle cells and establishes lifelong latent infection. Central nervous system could be affected by this herpesvirus in primary infection and reactivation and EBV-DNA is not an uncommon finding in CSF in HIV-infected population. The significance of our research is in identifying the presence of a link between HIV and EBV CNS replication.

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Lupia, T., Milia, M. G., atzori, c., Audagnotto, S., imperiale, d., mighetto, l., pirriatore, v., Gregori, G., lipani, f., Ghisetti, V., Bonora, S., Di Perri, G., Calcagno, A.. 2018-06-07. Epstein-Barr Virus May Contribute to Central Nervous System Involvement in HIV-positive Individuals. https://doi.org/10.1101/341354

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