Altered expression of fractalkine in HIV-1-infected astrocytes and consequences for the virus-related neurotoxicity

• Published in: Journal of neurovirology 2021-04, Vol.27 (2), p.279-301
• Main Authors: Sénécal, Vincent, Barat, Corinne, Gagnon, Marie-Thérèse, Vanasse, François, Leboeuf, Mathieu, Gosselin, David, Tremblay, Michel J.
• Format: Article
• Language: English
• Subjects: Biomedical and Life Sciences; Biomedicine; Immunology; Infectious Diseases; Neurology; Neurosciences; Virology
• ISSN: 1355-0284; 1538-2443
• DOI: 10.1007/s13365-021-00955-3

HIV-1 infection in the central nervous system (CNS) causes the release of neurotoxic products from infected cells which trigger extensive neuronal loss. Clinically, this results in HIV-1-associated neurocognitive disorders (HAND). However, the effects on neuroprotective factors in the brain remain poorly understood and understudied in this situation. HAND is a multifactorial process involving several players, and the complex cellular mechanisms have not been fully elucidated yet. In this study, we reported that HIV-1 infection of astrocytes limits their potential to express the protective chemokine fractalkine in response to an inflammatory environment. We next confirmed that this effect was not due to a default in its shedding from the cell surface. We then investigated the biological mechanism responsible for this reduced fractalkine expression and found that HIV-1 infection specifically blocks the interaction of transcription factor NF-κB on its promoter with no effect on other cytokines. Moreover, we demonstrated that fractalkine production in astrocytes is regulated in response to immune factors secreted by infected/activated microglia and macrophages. In contrast, we observed that conditioned media from these infected cells also trigger neuronal apoptosis. At last, we demonstrated a strong neuroprotective action of fractalkine on human neurons by reducing neuronal damages. Taken together, our results indicate new relevant interactions between HIV-1 and fractalkine signaling in the CNS. This study provides new information to broaden the understanding of HAND and possibly foresee new therapeutic strategies. Considering its neuro-protective functions, reducing its production from astrocytes could have important outcomes in chronic neuroinflammation and in HIV-1 neuropathogenesis.