Occludin Regulates HIV-1 Infection by Modulation of the Interferon Stimulated OAS Gene Family

Abstract

HIV-1-associated blood brain barrier (BBB) alterations and neurocognitive disorders are frequent clinical manifestations in HIV-1 infected patients. The BBB is formed by cells of the neurovascular unit (NVU) and sealed together by tight junction proteins, such as occludin (ocln). Pericytes are a key cell type of NVU that can harbor HIV-1 infection via a mechanism that is regulated, at least in part, by ocln. After viral infection, the immune system starts the production of interferons, which induce the expression of the 2'-5'-oligoadenylate synthetase (OAS) family of interferon stimulated genes and activate the endoribonuclease RNaseL that provides antiviral protection by viral RNA degradation. The current study evaluated the involvement of the OAS genes in HIV-1 infection of cells of NVU and the role of ocln in controlling OAS antiviral signaling pathway. We identified that ocln modulates the expression levels of the OAS1, OAS2, OAS3, and OASL genes and proteins and, in turn, that the members of the OAS family can influence HIV replication in human brain pericytes. Mechanistically, this effect was regulated via the STAT signaling. HIV-1 infection of pericytes significantly upregulated expression of all OAS genes at the mRNA level but selectively OAS1, OAS2, and OAS3 at the protein level. Interestingly no changes were found in RNaseL after HIV-1 infection. Overall, these results contribute to a better understanding of the molecular mechanisms implicated in the regulation of HIV-1 infection in human brain pericytes and suggest a novel role for ocln in controlling of this process.

Mitochondrial Antiviral Pathways Control Anti-Hiv Responses and Ischemic Stroke Outcomes via the Rig-1 Signaling and Innate Immunity Mechanisms

“…Reports from our laboratory 25 , 31 , 33 , 35 , 36 , including data presented in Fig 2I , have shown that ocln can regulate the extent of HIV-1 infection in various cell types, including brain pericytes. However, no studies have been performed in vivo demonstrating the influence of ocln on HIV replication in the brain.…”

“…Moreover, ocln can regulate HIV-1 budding from the infected cells by forming a complex with caveolin-1 and ALIX 35 . While the majority of research on the regulatory role of ocln on HIV-1 infection was performed on brain pericytes 25 , 31 , 35 , the findings were confirmed in human primary macrophages, differentiated monocytic U937 cells, and HEK-293 cells 43 .…”

“…Therefore, it is important that pericytes express high levels of HIV-1 co-receptors, CCR5 and CXCR4, and also CD4 77 . Importantly, HIV-1-mediated alterations of ocln expression have been linked to the regulatory mechanisms of HIV-1 infection 25 , 31 , 35 . Specifically, a decrease in cellular ocln levels results in enhanced HIV-1 replication, and the opposite effect is observed upon overexpression of ocln 31 , 35 .…”

“…Recently, our laboratory demonstrated that the ISG family 2´,5´-oligoadenylate synthetases (OAS) genes can regulate HIV-1 replication in BBB pericytes. However, the specific role of ISGs in HIV infection of this cell type remains largely unknown 25 .…”

“…Recent evidence indicates that BBB pericytes can be involved in immune responses, and that they can be infected by a variety of neurotropic viruses. Among them, brain pericytes can be infected by HIV-1, facilitating the release of the viral particles into the central nervous system (CNS) 25 , 30 – 36 . Among several host factors involved in HIV infection, the protein occludin (ocln) has recently been shown to play a key role in regulating the extent of HIV-1 infection 25 , 31 , 35 .…”