We propose to test our primary hypothesis that treatment with Peg-IFN-α-2b will result in a decrease in integrated HIV DNA in peripheral blood and tissue in chronically HIV-infected immune-reconstituted individuals (see section 3.1) in a prospective, interventional, 1-arm, open label clinical trial. To this end, we propose to enroll 25 HIV-1-infected subjects (please refer to power calculations in section 10.1 below) currently stably suppressed (> 1y with VL < 50 copies/ml) on ART and with CD4 count > 450 cells/µl.

We hypothesize that 20 weeks of treatment with Peg-IFN-alpha-2b, in the presence of HIV reactivation (i.e.: ART interruption), will result in activation of intrinsic and/or immune-mediated anti-HIV mechanisms resulting in a decrease in the levels of viral reservoir in chronically HIV-infected, immune-reconstituted individuals.

Inclusion Criteria:

• 18-65 years of age
• Body weight between 125 and 299 lbs
• Confirmed diagnosis of HIV-1 infection by western blot or by a documented HIV-1 viral load
• Currently receiving ART and on ART for > 1 year
• VL < 50 copies/ml for ≥ 1 year, with at least 2 measurements in the previous year, 1 viral "blip" with VL< 400 copies/ml allowed
• HIV viral load of <50 copies/ml at screening.
• CD4 >450 cells/µL at screening.
• A negative ECG if >45yrs men/>55yrs women years of age or if below these years of age but with two added risk factors for coronary artery disease [smoking, hypertension (BP >140/90 or on antihypertensive medications), low HDL (<40 mg/dL), family history of premature CHD (<55 yrs males/<65 females)] or a Framingham score > 15% (men) or 10% (women))

Exclusion Criteria:

• Confirmed clinical history of developing resistance to ART regimens that resulted in treatment changes

• Receiving didanosine as part of the participant's ART regimen at the time of screening

• Ongoing treatment with Isoniazide, pyrazinamide, Rifabutin, Rifampicin, Diadenosine Ganciclovir, Valgancyclovir, Oxymetholone, Thalidomide or Theophylline.

• Use of any investigational drug within 30 days prior to screening

• History or current use of immunomodulatory therapy for over 2 weeks during the 6 months prior to enrollment, including, but not limited to: IFN-alpha or gamma (recombinant or pegylated), systemic corticosteroids (nasal or pulmonary steroids will be allowed; systemic cancer chemotherapy/irradiation; cyclosporin; tacrolimus (FK-506); OKT-3; any Interleukin, including IL-2; cyclophosphamide; methotrexate; IVIG (gamma globulin); G/M-CSF; hydroxyurea; thalidomide; pentoxifylline; thymopentin; thymosin; dithiocarbonate; polyribonucleotide.

• History of adverse or allergic reactions to any type-1 interferon (e.g. IFN-alpha2a, IFN-α2b, IFN-beta)

• History of severe depression, or ongoing moderate depression determined by PHQ-9 at screening

• Type I diabetes mellitus, or type II diabetes mellitus that is not controlled with oral agents and/or insulin.

• Prior diagnosis of multiple sclerosis or other neurodegenerative disorders

• Significant co-existing lab abnormalities including:

  1. Anemia (Hgb <9.1 mg/dl men, <8.9 mg/dl women)
  2. WBC <2000 cells/µl
  3. Absolute neutrophil count (ANC) <1200 cells/ µl
  4. Platelet count <60,000 cells/ µl
  5. Liver disease (AST/ALT > 2.5x, Total Bilirubin > 1.5x upper limits of norm (ULN), or Total Bilirubin >3x ULN if receiving indinavir OR Atazanavir)
  6. Renal disease (creatinine > 2x upper normal limits or creatinine clearance <60mg/dl (by Crockoff-Gault)

• Chronic HCV infection (HCV viremia), or HBV Ag positive and/ or HBV viremia (Notice: subjects with prior HCV infection with a documented sustained virologic response with treatment finishing >1 year prior to screening are eligible for enrollment).

• Liver cirrhosis or hepatic decompensation with Child Pugh score > 6

• History of major organ transplantation with an existing functional graft.

• Evidence of OI or other active infectious diseases or active malignancies

• Active Autoimmune diseases, including autoimmune hepatitis

• History of retinopathy or clinically significant ophthalmologic disease on eye exam performed within 6 months prior to initiation of IFN

• Pregnancy, actively attempting to become pregnant, or breastfeeding

• Body weight under 125 lbs or over 300 lbs

• Other conditions, such as active drug/alcohol abuse or dependence which would interfere with study compliance