Baricitinib reverses HIV-associated neurocognitive disorders in a SCID mouse model and reservoir seeding in vitro

• Published in: Journal of neuroinflammation 2019-09, Vol.16 (1), p.182-182, Article 182
• Main Authors: Gavegnano, Christina, Haile, Woldeab B, Hurwitz, Selwyn, Tao, Sijia, Jiang, Yong, Schinazi, Raymond F, Tyor, William R
• Format: Article
• Language: English
• Subjects: AIDS Dementia Complex - pathology; AIDS Dementia Complex - virology; Animal cognition; Animals; Antiretroviral therapy; Azetidines - pharmacology; Baricitinib; Blood-brain barrier; CD45 antigen; Cell activation; Central nervous system; Cognition; Cognitive ability; Cognitive disorders; Complications and side effects; Development and progression; Disease Models, Animal; Drug dosages; Drug therapy; Encephalitis; Experiments; Flow cytometry; Glial fibrillary acidic protein; Gliosis; HIV; HIV infections; HIV-associated neurocognitive disorders; Human immunodeficiency virus; Humans; Infections; Inflammation; Interleukin 6; JAK inhibitor; Lymphocytes; Lymphoid cells; Macrophages; Mice; Mice, SCID; Microglia; Monocytes; Mononuclear phagocytes; Neuroinflammation; Neuronal-glial interactions; Object recognition testing; Patient outcomes; Rheumatoid arthritis; Safety; Studies; Sulfonamides - pharmacology; Tumor necrosis factor-α; Virus Activation - drug effects; Virus Latency - drug effects; Virus Replication - drug effects; α-Interferon
• ISSN: 1742-2094; 1742-2094
• DOI: 10.1186/s12974-019-1565-6

Since HIV-associated neurocognitive disorders (HANDs) occur in up to half of HIV-positive individuals, even with combined antiretroviral therapy (cART), adjunctive therapies are needed. Chronic CNS inflammation contributes to HAND and HIV encephalitis (HIVE). Baricitinib is a JAK 1/2 inhibitor approved in the USA, EU, and Japan for rheumatoid arthritis, demonstrating potent inhibition of IL-6, D-dimer, CRP, TNF-α, IFN-α/β, and other pro-inflammatory cytokines. Our modified murine HAND model was used to evaluate the ability of baricitinib to cross the blood-brain barrier (BBB) and modulate monocyte/macrophage-driven HAND. Severity of HAND was measured by assessing cognitive performance of low- and high-dose baricitinib treated versus untreated HAND mice. The severity of brain neuroinflammation was evaluated in these mouse groups after flow cytometric analyses. We also assessed the ability of baricitinib to block events in myeloid and lymphoid cells in vitro that may undergird the persistence of HIV in the central nervous system (CNS) in primary human macrophages (Mϕ) and lymphocytes including HIV replication, HIV-induced activation, reservoir expansion, and reservoir maintenance. In vivo, both doses of 10 and 50 mg/kg qd baricitinib crossed the BBB and reversed behavioral abnormalities conferred by HIV infection. Moreover, baricitinib significantly reduced HIV-induced neuroinflammation marked by glial activation: activated microglia (MHCII /CD45 ) and astrogliosis (GFAP). Baricitinib also significantly reduced the percentage of p24+ human macrophages in mouse brains (p