Inclusion Criteria:
- HIV infected on continuous antiretroviral therapy (ART) with plasma HIV RNA <200 copies/ml for at least 12 months (on at least two previous clinic visits and confirmed at screening)
- Current cluster of differentiation 4 (CD4+) > 350 cells/microliter for at least twelve months (on at least two previous clinic visits and confirmed at screening)
- A primary diagnosis of Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) major depression, current, or Bipolar, depressed type as diagnosed by the SCID-V
- Score of ≥10 on the 9-item Patient Health Questionnaire (PHQ-9)
- Off all antidepressant or other psychotropic therapy (e.g. mood stabilizers, antipsychotics, and sedative hypnotics) for at least 4 weeks (8 weeks for fluoxetine) or on a stable psychotropic regimen for at least 4 weeks prior to baseline visit
- Significant anhedonia as reflected by a score ≥ 2 on item #1 of the PHQ-9
- CRP≥2mg/L
- Women of reproductive age will have a negative serum pregnancy test at study entry and both men and women must agree to adequate contraception while
Exclusion Criteria:
- < 18 years of age or > 65 years of age
- Pregnancy or breastfeeding
- Significant hematological abnormalities at screening (ANC < 1500, Hgb<10, platelet< 100,000)
- History of progressive multifocal leukoencephalopathy
- Untreated latent tuberculosis infection (which will be screened for prior to entry)
- Having taken the following immunosuppressive medications within the past 6 months:
1. Oral corticosteroids
2. Biologic treatments such as etanercept, infliximab, certolizumab, adalimumab, golimumab, tocilizumab, abatacept, Ustekinumab, ixekizumab, secukinumab, or anakinra
3. Cyclophosphamide (or any other cytotoxic agent), belimumab, or anifrolumab (or another anti-interferon (IFN) therapy)
4. Rituximab, any other B cell depleting therapies, or intravenous immunoglobulin (IVIg)
5. any Janus kinase (JAK) inhibitor
- History of deep venous thrombosis
- Cardiovascular disease:
1. Coronary artery disease or history of myocardial infarction
2. Congestive heart failure with left ventricular ejection fraction ≤40% per American Heart Association guidelines
3. Stroke history
- Hematologic malignancies including lymphoma and leukemia
- Major surgery within 8 weeks prior to screening or will require major surgery during the study
- Current or recent (<4 weeks prior to randomization) clinically serious viral (including coronavirus disease 2019 (COVID-19)), bacterial, fungal, or parasitic infection or any other active or recent infection
- Symptomatic herpes simplex at the time of randomization
- Symptomatic herpes zoster infection within 12 weeks prior to randomization
- History of disseminated/complicated herpes zoster (for example, ophthalmic zoster or CNS involvement)
- Positive test for hepatitis B virus (HBV) defined as:
1. positive for hepatitis B surface antigen (HBsAg), or
2. positive for hepatitis B core antibody (HBcAb) and positive for hepatitis B virus deoxyribonucleic acid (HBV DNA)
- Hepatitis C virus (HCV) infection (hepatitis C antibody-positive and HCV ribonucleic acid \[RNA\]-positive)
- Cirrhosis of the liver from any cause
- Any of the following specific abnormalities on screening laboratory tests:
1. alanine transaminase (ALT) or aspartate aminotransferase (AST) >2 x upper limits of normal (ULN)
2. alkaline phosphatase (ALP) ≥2 x ULN
3. total bilirubin ≥1.5 x ULN (with the exception of patients on atazanavir, who must have total bilirubin <2 x ULN)
- Chronic kidney disease with estimated glomerular filtration rate (eGFR) <40 mL/min/1.73 m\^2
- History of any (non-mood-related) psychotic disorder; active psychotic symptoms of any type; substance abuse/dependence within 6 months of study entry, as determined by severe combined immunodeficiency (SCID)
- A positive urine drug screen for illicit drugs at any time during the study excluding marijuana
- An active suicidal plan as determined by a score >3 on item #3 on the Hamilton Rating Scale for Depression (HAM-D)
- An active eating disorder or antisocial personality disorder
- History of dementia
- Chronic use of glucocorticoid containing medications or minocycline within 2 weeks of baseline or at any time during the study
- Any contraindication for MRI scanning
- Failure of more than 2 antidepressant trials (at least 6 weeks at recommended dose) in the current episode or 5 antidepressant trials lifetime
- BMI >42 (to exclude severe obesity) or at the investigator's discretion based on the patient's ability to fit in the MRI scanner