HIV-1-Gag Conserved-Element DNA Vaccine as Therapeutic Vaccination in HIV-Infected Persons With Viral Suppression on Antiretroviral Therapy

This study will evaluate the safety, immunogenicity, and preliminary assessment of efficacy
of a novel vaccine encoding conserved elements (CE) of the HIV-1 Gag core protein, p24Gag, as
a therapeutic vaccine in HIV-1 infected persons who are on antiretroviral therapy (ART).

The study will randomly assign participants to one of three groups. Participants in Arm 1
will receive p24CE1/2 pDNA vaccine at Weeks 0 and 4, followed by p24CE1/2 pDNA admixed with
full-length p55^gag pDNA vaccine at Weeks 12 and 24. Participants in Arm 2 will receive
full-length p55^gag pDNA vaccine at Weeks 0, 4, 12, and 24. Participants in Arm 3 will
receive placebo at Weeks 0, 4, 12, and 24.

Study visits will occur at Weeks 0, 4, 6, 12, 24, 26, and 48 and may include physical
examinations and blood and urine collection. Some participants may undergo leukapheresis and
stool sample collection.

Inclusion Criteria:

- HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or
chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and
confirmed by a licensed Western blot or a second antibody test by a method other than
the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 RNA assay. NOTE:
The term "licensed" refers to a U.S. FDA-approved kit, which is required for all IND
studies. WHO (World Health Organization) and CDC (Centers for Disease Control and
Prevention) guidelines mandate that confirmation of the initial test result must use a
test that is different from the one used for the initial assessment. A reactive
initial rapid test should be confirmed by either another type of rapid assay or an
E/CIA that is based on a different antigen preparation and/or different test principle
(e.g., indirect versus competitive), or a Western blot or a plasma HIV-1 RNA viral
load.

- Receiving a stable ART regimen for a minimum of 2 years prior to study entry and with
no changes in the components of their antiretroviral therapy for at least 90 days
prior to study entry. One of the agents must include an integrase inhibitor,
non-nucleoside reverse transcriptase inhibitors (NNRTI), or a boosted-protease
inhibitor (PI). NOTE: Changes in the ART regimen for reasons other than virologic
breakthrough during the 2-year period are acceptable.

- CD4 cell count greater than 500 cells/mm^3 obtained within 60 days prior to study
entry at any U.S. laboratory that has a CLIA certification or its equivalent.

- Nadir CD4 cell count greater than 350 cells/mm^3. NOTE: Candidate recall or
documentation is acceptable.

- One documented plasma HIV-1 RNA that is below the limit of detection of an
FDA-approved assay between 24 and 36 months prior to the screening HIV-1 RNA, one
documented plasma HIV-1 RNA that is below the limit of detection of an FDA-approved
assay between 12 and 24 months prior to the screening HIV-1 RNA, and one documented
HIV-1 RNA that is below the limit of detection of an FDA-approved assay collected
fewer than 12 months prior to the screening HIV-1 RNA (see the protocol). NOTE: A
single, unconfirmed plasma HIV-1 RNA above the limit of detection but less than 400
copies/mL is allowed if followed by an HIV-1 RNA below detectable limits, but not in
the 6 months prior to screening.

- Plasma HIV-1 RNA level that is below the limit of detection of an FDA-approved assay
within 60 days prior to study entry.

- The following laboratory values obtained within 60 days prior to entry by any U.S.
laboratory that has a CLIA certification or its equivalent:

- Absolute neutrophil count (ANC) greater than or equal to 750 cells/mm^3

- Hemoglobin greater than or equal to 10.0 g/dL for men and greater than or equal
to 9.0 g/dL for women

- Platelet count greater than or equal to 100,000/mm^3

- Prothrombin time (PT), partial thromboplastin time (PTT), and INR less than 1.5 x
upper limit of normal (ULN)

- Creatinine clearance greater than or equal to 50 mL/min estimated by the
Cockcroft-Gault equation. NOTE: A program for calculating creatinine clearance by
the Cockcroft-Gault method is available on www.fstrf.org.

- Alanine aminotransferase (ALT) (SGPT) less than or equal to 2.5 x ULN

- Total bilirubin less than 1.6 x ULN (if on atazanavir less than or equal to 5 x
ULN)

- HCV antibody negative result within 60 days prior to study entry or, if the HCV
antibody result is positive, a negative HCV RNA result prior to study entry.

- Negative HBsAg result obtained within 60 days prior to study entry.

- Men and women age greater than or equal to 18 to less than or equal to 65 years

- Documentation of the availability of the stored pre-entry peripheral blood mononuclear
cell (PBMC) specimens for T cell assays. Sites must receive confirmation from the
processing lab via phone, e-mail, or fax that specimens have been entered into the
ACTG Laboratory Data Management System (LDMS).

- Ability and willingness of participant or legal guardian/representative to provide
informed consent

- Ability and willingness of participant to continue cART throughout the study.

- For females of reproductive potential, negative serum or urine pregnancy test within
15 days prior to entry by any clinic or laboratory that has a CLIA certification or
its equivalent, or is using a point of care (POC)/CLIA-waived test. NOTE: Reproductive
potential is defined as girls who have reached menarche and women who have not been
post-menopausal for at least 12 consecutive months with follicle-stimulating hormone
(FSH) greater than or equal to 40 IU/mL or 24 consecutive months if an FSH is not
available, or have not undergone surgical sterilization (e.g., hysterectomy, bilateral
oophorectomy, tubal ligation, or salpingectomy).

- If participating in sexual activity that could lead to pregnancy, willingness of
female participants to use two forms of effective contraception while receiving study
medication and for 3 months after stopping study medication is required.

- NOTE A: Effective forms of contraception include:

- Barrier methods (condoms [male or female] with or without a spermicidal agent,
diaphragm, or cervical cap [with spermicide])

- Hormone-based contraception (oral, patch, parenteral, implants, or vaginal ring)

- Intrauterine device (IUD)

- NOTE B: If the female participant is not of reproductive potential (women who are
post-menopausal as defined above, or women who have undergone surgical
sterilization [e.g., hysterectomy, bilateral oophorectomy, tubal ligation or
salpingectomy]), she is eligible without requiring the use of a contraceptive
method. Acceptable documentation of surgical sterilization and menopause is
participant-reported history.

- Indication of willingness to have the leukapheresis procedure. NOTE: Leukapheresis
will be required if the study has reached 50% of the accrual target and less than 20
participants have agreed to have the leukapheresis procedure.

Exclusion Criteria:

- History of malignancy within the last 5 years prior to study entry or current
malignancy requiring cytotoxic therapy. NOTE: A history of non-melanoma skin cancer
(e.g., basal cell carcinoma or squamous cell skin cancer) is not exclusionary.

- History of HIV-related opportunistic infections within the last 5 years prior to study
entry. NOTE: The CDC classifications are available on the A5369 protocol-specific
webpage (PSWP).

- History of or active autoimmune disorders including but not limited to inflammatory
bowel diseases, scleroderma, severe psoriasis, myocarditis, uveitis, pneumonitis,
systemic lupus erythematosus, rheumatoid arthritis, optic neuritis, myasthenia gravis,
adrenal insufficiency, autoimmune thyroiditis, or sarcoidosis. NOTE: For questions
related to the definition of autoimmune disorders, sites should contact the A5369 core
team per the Study Management section.

- Bleeding diathesis or condition associated with prolonged bleeding time that would
contraindicate IM injection.

- A skin-fold measurement of the cutaneous and subcutaneous tissue for eligible
injection sites (on the medial deltoid or vastus lateralis muscles) that does not
exceed 50 mm. NOTE: The skin-fold measurement must be conducted in accordance with the
procedure described in the TDS-IM Instructions for Use (see A5369 MOPS).

- Use of any prior HIV vaccine (prophylactic and/or therapeutic) within 1 year prior to
study entry. NOTE: A documented study placebo recipient may participate.

- Use of any investigational treatment within 6 months prior to study entry.

- Any licensed or experimental non-HIV vaccination (e.g., hepatitis B, influenza,
pneumococcal polysaccharide) within 4 weeks prior to study entry. NOTE: Participants
with anticipated need to receive non-HIV vaccinations within 2 weeks prior to the
scheduled study vaccination #2 (week 4), or #3 (week 12), or #4 (week 24) injection
should be excluded.

- Use of any infusion blood product or immune globulin within 3 months prior to study
entry.

- Acute or serious illness, in the opinion of the site investigator, requiring systemic
treatment and/or hospitalization within 30 days prior to entry.

- Use of immunomodulators (e.g., interleukins, interferons, cyclosporine), systemic
cytotoxic chemotherapy, or investigational therapy within 60 days prior to study
entry. NOTE: Participants receiving stable physiologic glucocorticoid doses, defined
as prednisone less than or equal to 10 mg/day or the equivalent, will not be excluded.
Stable physiologic glucocorticoid doses should not be discontinued for the duration of
the study. In addition, participants receiving inhaled or topical corticosteroids will
not be excluded.

- Intent to use immunomodulators (e.g., IL-2, IL-12, interferons, or TNF modifiers)
during the course of the study.

- Known or suspected hypersensitivity to any vaccine component, including
hypersensitivity to amide-type local anesthetics, such as lidocaine (Xylocaine),
mepivacaine (Polocaine/Carbocaine), etidocaine (Duranest), bupivacaine (Marcaine), or
prilocaine.

- Current use of any electronic stimulation device, such as cardiac demand pacemakers,
automatic implantable cardiac defibrillator, nerve stimulators, or deep brain
stimulators.

- History of cardiac arrhythmia or palpitations (e.g., supraventricular tachycardia,
atrial fibrillation, frequent ectopy, or sinus bradycardia [i.e., less than 50 beats
per minute on exam]) prior to study entry. NOTE: Sinus arrhythmia is not excluded.

- History of syncope or fainting episode within 1 year of study entry.

- Seizure disorder or any history of prior seizure.

- Extensive tattoos covering the site of administration (upper left and right medial
deltoid muscles and left and right vastus lateralis muscles).

- Presence of any surgical or traumatic metal implants at the site of administration
(medial deltoid or vastus lateralis muscles).

- Immune deficiency other than HIV.

- Breastfeeding or pregnancy.

- Active drug or alcohol use or dependence that, in the opinion of the site
investigator, would interfere with adherence to study requirements.

- Current HCV antiviral therapy.

- Type I or type II diabetes mellitus.

- Weight less than 50 kg or greater than 200 kg.

- Known to have been started on antiretroviral therapy within 3 months of the presumed
or known date of first acquiring HIV-1 infection; i.e., treated during acute HIV-1
infection.