A Phase I Study of T-Cells Genetically Modified at the CCR5 Gene by Zinc Finger Nucleases SB-728mR in HIV-Infected Patients

Inclusion Criteria:

- HIV-1 infection, as documented by a rapid HIV test or any FDA-approved HIV-1 Enzyme or
Chemiluminescence Immunoassay (E/CIA) test kit and confirmed by Western blot at any
time prior to study entry or HIV antigen, plasma HIV-1 RNA, or second antibody test by
a method other than rapid HIV and E/CIA. Alternatively, if a rapid HIV test or any
FDA-approved HIV-1 Enzyme or Chemiluminescence Immunoassay (E/CIA) test kit is not
available, two HIV-1 RNA values ≥ 2000 copies/mL at least 24 hours apart performed by
any laboratory that has CLIA certification, or its equivalent, may be used to document
infection.

- CD4+ T cell count of ≥450 cells/mm3 at screen; and a documented CD4 nadir of not lower
than 200 cells/mm3.

- Adequate venous access and no other contraindications for leukapheresis.

- Laboratory values obtained at screen:

1. Hemoglobin: ≥ 10.0 (males); ≥ 9.5 (females) g/dL

2. Absolute neutrophil count (ANC): ≥ 1000/mm3

3. Platelet count: ≥ 100,000/mm3

4. 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 or until undergoing the analytical treatment interruption.

- Be male or female, 18 years of age and older.

- Ability and willingness of subject to provide informed consent.

- Have a Karnofsky Performance Score of 70 or higher.

- Have no polymorphisms in the CCR5 ZFN target region as determined by Cel I snp assay
at screening.

- Subjects in Cohorts 2 and 3: LVEF > or equal to 40%

- Clinically stable on their first or second HAART regimen. Changes while the patient
HIV viral load is undetectable does not count toward the number of ART regimens used,
only changes made for virologic failure (for example an individual switching from an
NNRTI-based regimen to an integrase inhibitor based regimen while the HIV viral load
is undetectable will still be in their first regimen). Site investigator anticipates
that a fully active alternative ART regimen could be constructed in the event of
virologic failure on the current ART regimen. The current regimen should have no
changes within 4 weeks of enrollment. Subjects must be willing to continue on current
antiretroviral therapy for the duration of the study except for the duration of the 16
week analytical treatment interruption. NOTE: Subject's ART regimen must be in
accordance with the Department of Health and Human Services Document "Guidelines for
the Use of Antiretroviral Agents in HIV-1 Infected Adults and Adolescents."

- HIV-1 RNA undetectable by ultrasensitive assay copies/ml obtained at study screening
visit or within 60 days prior to study screening visit performed with an
ultrasensitive HIV-1 PCR assay. All subjects must have received at least 18 months of
therapy and have HIV-1 RNA <50 copies/mL using a FDA-approved assay for at least 48
weeks prior to enrollment. HIV-1 RNA must be measured at least once in the 24 weeks
prior to enrollment and at least 3 days before the screening measure. Single
determinations that are between ≥50 and <500copies/mL (i.e., blips) are allowed as
long as the preceding and subsequent determinations are <50 copies/mL. The screening
value may serve as the subsequent determination <50 copies/mL following a blip. NOTE:
subjects who have participated in other trials using ATI's will be permitted since
detectable virus during the interruption does not represent virologic failure. These
subjects should have at least 24 weeks of VL <50 copies/mL.

- Have a recorded viral load set point

Exclusion Criteria:

- Acute or chronic hepatitis B or hepatitis C infection (as further defined in section
6.3.4 and 6.3.8 of this protocol)

- Current or prior AIDS diagnosis.

- History of cancer or malignancy, with the exception of successfully treated basal cell
or squamous cell carcinoma of the skin

- History or any features on physical examination indicative of active or unstable
cardiac disease or hemodynamic instability. NOTE: subjects with a history of cardiac
disease may participate with a physician's approval.

- History or any features on physical examination indicative of a bleeding diathesis.

- Have been previously treated with any HIV experimental vaccine within 6 months prior
to screening, or any previous gene therapy using an integrating vector. Note: Subjects
treated with placebo in an HIV vaccine study will not be excluded if documentation
that they received placebo is provided.

- Use of chronic systemic corticosteroids, hydroxyurea, or immunomodulating agents
(e.g., interleukin-2, interferon-alpha or gamma, granulocyte colony stimulating
factors, etc.) within 30 days prior to study screening visit. NOTE: Recent or current
use of inhaled steroids is not exclusionary. If subjects are prescribed a brief course
of oral corticosteroids, the use should be limited to less than 7 days. Use of
steroids before apheresis and immune assessment blood draws should be discouraged as
it will affect white blood cell function.

- Breast-feeding, pregnant, or unwilling to use acceptable methods of birth control.

- Anticipated 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 site
investigator, would interfere with adherence to study requirements.

- Serious illness requiring systemic treatment and/or hospitalization within 30 days
prior to study screening visit.

- Asymptomatic baseline serum chemistry elevations in LFTs, bilirubin, lipase and serum
creatinine due to HAART medication are not exclusionary, when in the opinion of the
investigator, the abnormalities are not attributable to intrinsic hepatorenal disease.
Such baseline elevations must be due to HAART.

- Receipt of vaccination within 30 days prior to study screening visit. NOTE: It is
recommended that subjects enrolling into this study should have completed their
routine vaccinations (hepatitis A, hepatitis B, pneumococcus, and tetanus diphtheria
booster) at least 30 days prior to screening for the study.

- Have an allergy or hypersensitivity to study product excipients (human serum albumin,
DMSO and Dextran 40).