Autologous T-Cells Genetically Modified at the CCR5 Gene by Zinc Finger Nucleases SB-728 for HIV

Cohort 1 - Patients who have failed two more HAART regimens (6 subjects)

Cohort 2 - Patients doing well on a stable antiretroviral medication (6 subjects)

Cohort 3 - Patients who have an undetectable viral load on HAART who have exhibited suboptimal CD4+ T cell gains during long term antiretroviral therapy. This group will not participate in the structured treatment interruption. (6 subjects)

• Eligibility: Physical Exam, Medical History, Blood Draws for clinical labs and research.
• 1st Procedure to collect T cells (called apheresis)
• 2nd Procedure to collect T cells (called apheresis occurs ~3 weeks after 1st Apheresis)and Rectal Biopsy
• Clinic visit: Physical Exam, Blood Draw for clinical labs and research (~1 to 2 weeks after 2nd Apheresis)
• Infusion of ZFN modified T cells (~2weeks after Clinic Visit)

Cohort 1 and Cohort 3 only:

• Follow up Clinic Visits 48, 72 hours; 1,2,3,6 weeks; 2,3,6, 9 months after ZFN infusion.

Cohort 2 Only:

• Stop Antiretroviral Medications 4 Weeks after ZFN modified T cell Infusion.

• Follow-up Clinic Visits 6, 8, 10, 12, 16, weeks after ZFN modified T cell Infusion.

• Restart Antiretroviral Medications 20 weeks after ZFN modified T cell Infusion.

• Follow-up Clinic Visits: monthly visits until no detectable HIV found in blood.

Inclusion criteria

Cohort 1 Only:

• Patients who have been on two more HAART regimens and have failed due to resistance or tolerance (no changes to treatment within 4 weeks of study entry), and who have no viable treatment options likely to result in complete viral suppression.
• CD4+ T cell count of ≥200 cells/mm3
• HIV-1 RNA ≥2000 copies/mL obtained within 60 days prior to study entry performed with an ultrasensitive HIV-1 PCR assay.
• Two HIV-1 RNA levels <150,000 copies/mL obtained within 60 days prior to study entry performed with an ultrasensitive HIV-1 PCR assay. These HIV-1 RNA measurements must be at least 48 hours apart and may include the HIV-1 RNA measurement done at the time of the screening visit.
• Ongoing treatment with HIV entry inhibitors such as enfurvitide or maraviroc are excluded

Cohort 2 Only:

• On a stable antiretroviral medication (no changes to treatment within 4 weeks of study entry) and be willing to continue on current antiretroviral therapy for the duration of the study until undergoing structured treatment interruption.
• CD4+ T cell count of ≥450 cells/mm3 at screen; and a documented CD4 nadir of not lower than 300 cells/mm.
• HIV-1 RNA undetectable by ultrasensitive HIV PCR assay obtained within 60 days prior to study entry performed with an ultrasensitive HIV-1 PCR assay.

Cohort 3 only:

• On a stable antiretroviral medication (no changes to treatment within 4 weeks of study entry) and be willing to continue on current antiretroviral therapy for the duration of the study.
• CD4+ T cell count that is persistently <500 cells/mm3 despite at least 2 years of stable HAART and >200 cells/mm3 at screen
• Subjects must have received at least 2 continuous years of therapy and have had undetectable viral loads by ultrasensitive assay since 6 months of therapy. Subjects who have had a single viral load blip at any point in this time, or who experience intermittent isolated episodes of detectable low-level viremia (detectable but <1000 copies RNA/mL; blips) will remain eligible.
• Subjects who are currently taking maraviroc or have received maraviroc within 6 months of study entry are excluded.

Inclusion for Cohort 1, Cohort 2, Cohort 3:

• HIV-1 infection, as documented by ELISA and confirmed by Western blot at any time prior to study entry. HIV-1 culture, HIV-1 antigen, plasma HIV-1 RNA, or a second antibody test by a method other than ELISA is acceptable as an alternative confirmatory test.
• Adequate venous access and no other contraindications for leukapheresis.
• Laboratory values obtained at screen. Hemoglobin: ≥ 10.0 (males); ≥ 9.5 (females) g/dL Absolute neutrophil count (ANC): ≥ 1000/mm3 Platelet count: ≥ 100,000/mm3 Serum creatinine: ≤ 1.5 mg/dL (133µ mol/L) Aspartate aminotransferase (AST) or alanine aminotransferase (ALT): ≤ 2.5 times the upper limit of normal (ULN).
• Subjects must be willing to comply with study-mandated evaluations; including not changing their antiretroviral regimen (unless medically indicated) for 2 months in step 2 (Cohort 1) or until undergoing structured treatment interruption (Cohort 2).
• Karnofsky Performance Score of 70 or higher

Exclusion criteria

• Acute or chronic hepatitis B or hepatitis C infection
• Current or prior AIDS diagnosis (Cohort 1 and 2 only)
• History of cancer or malignancy, (basal cell or squamous cell carcinoma of the skin allowed)
• History or problems with uncontrolled heart disease, bleeding or hemodynamic instability.
• Have been previously treated with any HIV experimental vaccine within 6 months prior to screening, or any previous gene therapy using an integrating vector.
• Use of the following medications within the last 30 days: chronic corticosteroids, hydroxyurea, or immunomodulating agents (e.g., interleukin-2, interferon-alpha or gamma, granulocyte colony stimulating factors, etc.)
• Breast-feeding, pregnant, or unwilling to use acceptable methods of birth control.
• Use of aspirin, dyprydamole, warfarin or any other medication that is likely to affect platelet function or other aspects of blood coagulation during the 2-week period prior to leukapheresis.
• Active drug or alcohol use or dependence that in the opinion of the investigator, would interfere with adherence to study requirements
• Serious illness requiring systemic treatment and/or hospitalization within 30 days prior to study entry.
• Receipt of a vaccination within 30 days prior to study entry.
• Have an allergy or hypersensitivity to study product excipients (human serum albumin, DMSO and Dextran 40).
• Currently taking medications called HIV entry inhibitors such as enfuvirtide or maraviroc