Abstract
BackgroundSince 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.MethodsOur 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.ResultsIn 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 < 0.05 versus HAND mice; t test). In vitro, baricitinib significantly reduced markers of persistence, reservoir size, and reseeding in Mϕ.ConclusionThese results show that blocking the JAK/STAT pathway reverses cognitive deficits and curtails inflammatory markers in HAND in mice. Our group recently reported safety and tolerability of ruxolitinib in HIV-infected individuals (Marconi et al., Safety, tolerability and immunologic activity of ruxolitinib added to suppressive ART, 2019), underscoring potential safety and utility of JAK inhibitors for additional human trials. The data reported herein coupled with our recent human trial with JAK inhibitors provide compelling preclinical data and impetus for considering a trial of baricitinib in HAND individuals treated with cART to reverse cognitive deficits and key events driving viral persistence.
Highlights
Of the estimated 38 million people living with HIV-1 infection, HIV-associated neurocognitive disorders (HANDs) occur in up to 50%, even with combined antiretroviral therapy [1,2,3,4]
We established a murine HAND model that comprises intracranial (IC) injection of HIV-1 infected human monocyte-derived macrophages (MDM) into a SCID mouse with primary readouts of cognitive dysfunction measured by maze learning and pathological indices quantified with immunohistochemistry that included amounts of astrogliosis and mononuclear phagocytes and decreases in MAP2 immunostaining [6,7,8,9]
We demonstrate that baricitinib crosses the blood-brain barrier (BBB), reverses object recognition testing (ORT) abnormalities, and decreases HAND/HIV encephalitis (HIVE) pathological markers in a SCID mouse HAND model
Summary
Of the estimated 38 million people living with HIV-1 infection, HIV-associated neurocognitive disorders (HANDs) occur in up to 50%, even with combined antiretroviral therapy (cART) [1,2,3,4]. Animal models that recapitulate behavioral and phenotypic events that define HAND have proven essential to investigating the correlate mechanism(s) of disease and development of novel therapeutic strategies [5,6,7,8,9]. The model incorporates object recognition testing (ORT) to demonstrate mild behavioral deficits in HAND mice prior to and after treatment with novel agents [10]. 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. 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 proinflammatory cytokines
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