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Principal Investigator: Christina Gavegnano
Organization: VETERANS HEALTH ADMINISTRATION
Fiscal Year: 2024
Funding agency: Veterans Affairs
A major barrier to HIV eradication is maintenance of latently infected cells in people living with HIV (PWH). The
Veteran population of PWH is nearly 2.5-fold greater versus non-Veteran individuals living in the United States,
underscoring a major unmet need within the United States Veteran's population for safe, specific agents that
can cure HIV and prevent or reverse associated co-morbidities. Chronic inflammation despite suppressive ART
drives HIV persistence and co-morbidities, including cardiovascular disease, frailty, diabetes, and HIV-
associated neurocognitive dysfunction (HAND). The Janus Kinase Signal Transducer and Activator of Signal
Transduction (Jak-STAT) pathway is a major mechanism of elevated immune dysregulation, even during viral
suppression. In viremic individuals, elevated pSTATs including pSTAT5 are associated with increased reservoir
size, viral loads, and decreased CD4+ T cell counts, underscoring the direct link between the Jak-STAT pathway
and the HIV-1 reservoir. Our team (Vincent Marconi (VAMC) William Tyor (VAMC) and Christina Gavegnano)
has extensively studied the class of Jak 1/2 inhibitors (indication HIV-1), including a first-generation Jak 1/2
inhibitor ruxolitinib, and demonstrated in a recently completed multi-site Phase 2a ACTG-sponsored study
(A5336;n=60) that ruxolitinib is safe, well-tolerated, and reduces key markers of immune activation associated
with HIV-1 persistence (HLA-DR/CD38, sCD14, and cellular lifespan marker bcl-2). We also showed a reduction
in the HIV-1 reservoir in individuals with higher baseline frequency of integrated HIV-1 DNA, demonstrating proof-
of-concept that Jak 1/2 inhibition can reduce the reservoir in a clinical setting. Furthermore, we observed that
ruxolitinib, in an in vitro model of HIV-1-infection in total memory CD4+ T cells, pushes differentiation of central
memory cells (TCM) to a shorter lived phenotype (effector memory T cells-TEM), which could also induce HIV-
1 reservoir decay. Baricitinib is a second-generation Jak 1/2 inhibitor (FDA approved for rheumatoid arthritis and
COVID-19), presenting a markedly improved safety profile versus ruxolitinib including approval for chronic long-
term use (including children), once daily dosing and renal clearance (making drug-drug interactions with
hepatically cleared agents unlikely; critical for add-on to ART). We have shown that baricitinib significantly
reduces the HIV-1 reservoir in primary T cells and reverses HIV-1 persistence markers and inflammation (murine
model). We also demonstrated that baricitinib confers substantial improvement of CD4/CD8 HIV-specific effector
function, boosting natural immune function that may i) enhance reservoir decline and ii) block or prevent
inflammatory driven co-morbidities in PWH. However, how baricitinib can confer reservoir reduction in ex vivo
patient samples, and in a dynamic in vivo (murine) model of systemic infection, remains unclear. We will define
the multi-functional action of baricitinib, a Jak ½ inhibitor developed by our team for treatment of viral infections
including HIV and COVID-19, towards control HIV reservoirs and persistence. This will be done by leveraging
our now-enrolling Phase2a study for baricitinib towards reduction of HIV-1 reservoir in the CNS
(NCT05452564) across peripheral blood and cerebral spinal fluid samples from the study, and existing VA
cohorts from Dr. Vincent Marconi (VA, Emory). Additional mechanisms will be bolstered by collaboration with
Dr. William Tyor (VA and Emory) using the humanized murine model of HIV-1 infection. Data will streamline
translation to additional human studies in the Veteran PWH population, for comorbidities and eventual HIV cure.
Terms: <0-11 years old><AACTG><ACTG><AIDS Virus><AIDS clinical trial group><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Antiinflammatory Effect><Atrophic Arthritis><B cell lymphoma 2><B-Cell CLL/Lymphoma 2 Gene><B-cell lymphoma/leukemia-2><BCL2><BCL2 gene><Bcl-2><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CD8><CD8B><CD8B1><CD8B1 gene><COVID-19><CV-19><Cardiovascular Diseases><Cell Body><Cell Communication and Signaling><Cell Count><Cell Number><Cell Signaling><Cells><Cellular Immune Function><Cerebrospinal Fluid><Child><Child Youth><Children (0-21)><Chronic><Clinical><Collaborations><Coronavirus Infectious Disease 2019><DNA><Data><Deoxyribonucleic Acid><Diabetes Mellitus><Dose><Drug Interactions><Drugs><Dysfunction><Enrollment><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><FDA approved><Frequencies><Functional disorder><Generations><HIV><HIV-1><HIV-I><HIV1><HLA-BR><HLA-BR Antigens><HLA-D-Related Antigens><HLA-DR><HLA-DR Antigens><HLA-MT><HLA-MT Antigens><Hepatic><Human><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human immunodeficiency virus 1><Immune><Immune Cell Activation><Immune Markers><Immunes><Immunologic Markers><In Vitro><Individual><Infection><Inflammation><Inflammatory><Interruption><Intracellular Communication and Signaling><Investigation><Investigators><JAK kinase><Janus kinase><LAV-HTLV-III><LYT3><Link><Lymphadenopathy-Associated Virus><Maintenance><Measures><Medication><Memory><Mice><Mice Mammals><Modeling><Modern Man><Modification><Murine><Mus><Myelogenous><Myeloid><Neurocognitive><Patients><Peripheral><Persons><Pharmaceutical Preparations><Phase><Phenotype><Physiopathology><Population><Prevention><Renal clearance function><Research Personnel><Researchers><Rheumatoid Arthritis><Safety><Sampling><Sampling Studies><Sentinel><Signal Transduction><Signal Transduction Pathway><Signal Transduction Systems><Signaling><Site><Systemic infection><T memory cell><T-Cells><T-Lymphocyte><T4 Cells><T4 Lymphocytes><TEM cells><Testing><Therapeutic Agents><Transducers><Translations><United States><Veterans><Viral><Viral Burden><Viral Diseases><Viral Load><Viral Load result><Virus Diseases><Virus-HIV><acquired immunodeficiency syndrome clinical trial group><anti-inflammatory effect><antiretroviral therapy><antiretroviral treatment><bcl-2 Genes><behavior change><biological signal transduction><cardiovascular disorder><ced9 homolog><cerebral spinal fluid><co-morbid><co-morbidity><cohort><comorbidity><coronavirus disease 2019><coronavirus disease-19><coronavirus infectious disease-19><diabetes><drug/agent><enroll><epigenetically><experiment><experimental research><experimental study><experiments><frailty><immune activation><immune function><immune-based biomarkers><immunological biomarkers><immunological markers><improved><in vitro Model><in vivo><inflammation marker><inflammatory marker><inhibitor><kids><life span><lifespan><memory CD4 T cell><memory CD4 T lymphocyte><memory T lymphocyte><military veteran><mouse model><murine model><pathophysiology><peripheral blood><prevent><preventing><renal clearance><rheumatic arthritis><spinal fluid><terminally differentiated effector memory (TEM) T cells><terminally differentiated effector memory T cells><thymus derived lymphocyte><translation><translation to humans><translational goal><translational mission><veteran population><viral infection><viral rebound><virus infection><virus rebound><virus-induced disease><youngster>