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Updated: Jan 18, 2026
Oral Combinational Antiretroviral Treatment in HIV-1 Infected Humanized Mice
Published on: October 6, 2022
Baricitinib reverses HIV-associated neurocognitive disorders in a SCID mouse model and reservoir seeding in vitro
Christina Gavegnano1,2, Woldeab B Haile2,3,4, Selwyn Hurwitz1,2
1Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University, Atlanta, GA, 30322, USA.
Insights
Baricitinib, a JAK inhibitor, effectively crosses the blood-brain barrier to reverse cognitive deficits and reduce neuroinflammation in a mouse model of HIV-associated neurocognitive disorders (HANDs). This study suggests baricitinib
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- HIV-associated neurocognitive disorders (HANDs) affect up to 50% of HIV-positive individuals, even with combination antiretroviral therapy (cART).
- Chronic central nervous system (CNS) inflammation is a key driver of HAND and HIV encephalitis (HIVE).
- Baricitinib, a Janus kinase (JAK) 1/2 inhibitor, effectively reduces pro-inflammatory cytokines implicated in CNS inflammation.
Purpose of the Study:
- To evaluate baricitinib's ability to cross the blood-brain barrier (BBB).
- To assess baricitinib's efficacy in modulating monocyte/macrophage-driven HAND in a murine model.
- To investigate baricitinib's in vitro effects on HIV persistence mechanisms in human myeloid and lymphoid cells.
Main Methods:
- A modified murine HAND model was employed to assess cognitive performance and neuroinflammation.
- Baricitinib's BBB penetration and reduction of glial activation (microglia, astrocytes) were evaluated.
- In vitro studies utilized primary human macrophages and lymphocytes to analyze baricitinib's impact on HIV replication, activation, and reservoir dynamics.
Main Results:
- Baricitinib (10 and 50 mg/kg qd) successfully crossed the BBB and reversed HIV-induced behavioral deficits in mice.
- Significant reductions in HIV-induced neuroinflammation, including glial activation and astrogliosis, were observed.
- Baricitinib decreased the percentage of p24+ human macrophages in mouse brains and reduced markers of HIV persistence in vitro.
Conclusions:
- Blocking the JAK/STAT pathway with baricitinib reverses cognitive deficits and reduces inflammatory markers in a murine HAND model.
- Preclinical data, supported by recent human trials of JAK inhibitors, support further investigation of baricitinib for HAND treatment.
- Baricitinib shows potential as an adjunctive therapy for HAND patients on cART to improve cognitive function and address viral persistence.
Background:
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.
Methods:
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.
Results:
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 < 0.05 versus HAND mice; t test). In vitro, baricitinib significantly reduced markers of persistence, reservoir size, and reseeding in Mϕ.
Conclusion:
These 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.
