Janus: A New Use of Jak Inhibitors for the Decay of HIV Reservoir Open Access
Reece, Monica (Summer 2024)
Abstract
Antiretrovirals do not target the HIV-1 reservoir in people with HIV (PWH), a major barrier to cure. Infected myeloid and CD4+ T cells exacerbate inflammation despite suppressed viremia. Chronic inflammation drives reservoir maintenance and reactivation in T cells and myeloid derived viral sanctuaries and contributes to non-AIDS comorbidities. We first evaluated the HIV-1 DNA reservoir in peripheral blood mononuclear cells (PBMC) and cerebrospinal fluid (CSF), as a surrogate for the central nervous system (CNS) reservoir, in PWH and associations to cognitive dysfunction. We observed CNS HIV correlated with worse executive function. Next, we evaluated ruxolitinib’s impact on the peripheral HIV-1 reservoir and immunomodulatory events driving persistence in PWH enrolled in ACTG A5336, an open-label randomized Phase 2a multi-site clinical trial. Participants (18-75 years old, on antiretroviral therapy (ART) ≥2 years, virologically suppressed, CD4+ count >350 cells/mm3, and without significant comorbidities except HIV or hypertension) were randomized to Jak inhibitor ruxolitinib plus ART (n=40) or ART alone (n=20) from week 0-5 and observed through week 12. Cellular markers, integrated DNA, and IPDA were measured peripherally at weeks 0, 5, and 12. Reservoir markers decayed in high baseline reservoir (HBR) participants on ruxolitinib by week 12 versus controls (p=0.0471). Cellular markers altered by ruxolitinib and associated with decay included pSTAT5+, pSTAT3+, BCL-2+KI67+, CD127+, and CD25+. We predict 99.99% decay in 2.83 years among HBR. These data are foundational for future human trials with Jak 1/2 inhibitors towards HIV-1 elimination. Clinical Trials Registration NCT02475655. Finally, we evaluated baricitinib, an FDA approved, 2nd generation Jak 1/2 inhibitor with a favorable safety, efficacy, and pharmacokinetic profile and once daily dosing. Preliminary in vitro data revealed that baricitinib did not impact HIV-GFP DNA or mRNA levels, significantly reduced IL-15-mediated pSTAT5 production, reduced active infection (p24+gp120+) in CD4+ T cells, and significantly reduced BCL-2 expression in both actively and latently (p24+gp120-) infected CD4+ T cells. These findings indicated that anti-viral effects of baricitinib are due to immunomodulation and that baricitinib would likely mirror the reservoir decay effect of ruxolitinib given a therapeutic duration ≥ 5 weeks as evidenced by reduction of reservoir maintenance, reactivation, and reseeding factors.
Table of Contents
Chapter I: Introduction.............................................................................................................................. 1
Overview...........................................................................................................................................1
Targeting Macrophage Dysregulation for Viral Infections: Novel Targets for Immunomodulators............ 3
Repurposing BCL-2 and Jak 1/2 Inhibitors: Cure and Treatment of HIV-1 and Other Viral Infections....... 35
Chapter II: The Identification of Intact HIV Proviral DNA from Human Cerebrospinal Fluid........................... 67
Chapter III: Ruxolitinib-Mediated HIV-1 Reservoir Decay in A5336 Phase 2a Trial ........................................ 92
Chapter IV: Effect of Baricitinib on HIV-1 Reservoir Maintenance In Vitro................................................... 141
Chapter V: Discussion.............................................................................................................................. 160
Appendices............................................................................................................................................. 178
Appendix I: Ex Vivo Differentiation of Resting CD4+ T Lymphocytes Enhances Detection of Replication Competent HIV-1 in Viral Outgrowth Assays............................................................................................. 178
Appendix II: A Rationale and Approach to the Development of Specific Treatments for HIV Associated Neurocognitive Impairment..................................................................................................................... 179
Appendix III: Honokiol Hexafluoro Confers Reversal of Neuropathological Markers of HIV Infection in a Murine SCID Model................................................................................................................................. 180
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