Study to Evaluate Effects of Vorinostat and HXTC on Persistent HIV-1 Infection in HIV-Infected Subjects Started on ART

Purpose: This study will test the use of special immune system cells called expanded
HIV-specific T Cell (HXTC) Therapy to stimulate the immune system to respond better to HIV.
HXTC Therapy will be given in combination with the drug Vorinostat (VOR) which has been shown
to stimulate some cells infected with HIV to become active and start making HIV virus. The
purpose of this study is to:

1. Evaluate the safety of a series of HXTC infusions in combination with serial doses of
VOR and

2. Help scientists evaluate ways of re-activating latent (non-active) HIV virus and
determine if the immune system can be made stronger to eliminate the activated HIV
virus.

Participants: HIV-infected men and women, ≥ 18 and < 65 years of age, with durable viral
suppression for ≥ 24 months as measured on standard HIV RNA assays. Eligible participants
must be on stable cART and have a CD4 count ≥ 350 cells/mm3. We plan to enroll up to 12
participants at UNC who complete all 6 Steps of this study.

Procedures (methods):

In Step 1 and prior to initiating the two series of VOR and HXTC combined therapies, all
participants will undergo study screening where they will be required to: 1. Demonstrate a
baseline measurement of the frequency of resting CD4 T cell infection ≥ 0.3 infected cells
per million as determined by QVOA, as a further decrease from this low frequency of infection
cannot be definitively measured given the QVOA assay threshold, and 2. Exhibit ex-vivo (Step
1) response to VOR

Participants progressing to Step 2 will receive 2 (two) doses of VOR 400 mg followed by a
leukapheresis. If an increase in cell-associated HIV RNA (ca-RNA) is observed in-vivo
following the single VOR dose, they will be eligible to donate cells for the manufacture of
HXTC (Step 3). Successful manufacturing of the HIV-1 antigen expanded specific T cells will
progress participants to combination treatment in Steps 4 and 5. In Steps 4 and Step 5,
participants will receive two series of VOR dosing and HXTC infusions, for a total 20 doses
of VOR 400 mg and 5 HXTC infusions.

In the first series (Step 4), participants will receive VOR 400 mg PO every 72 hours for 10
doses and 2 infusions of HXTC. The first HXTC infusion will be administered six hours after
the first dose of VOR (HXTC #1) and the 2nd HXTC infusion (HXTC #2) will occur 6 hours after
the 6th dose of VOR.

In the second series in Step 5, participants will receive an additional 10 doses of VOR 400
mg PO every 72 hours and 3 HXTC infusions. The first HXTC infusion in Step 5 (HXTC #3) will
occur 6 hours after the 11th dose of VOR (1st dose in Step 5), the 2nd HXTC infusion (HXTC
#4) will occur 6 hours after the 16th dose of VOR, and the 3rd HXTC infusion (HXTC #5) will
occur 1 - 3 days after the 20th dose of VOR. If there are insufficient cells manufactured to
allow 5 infusions, the first infusion in Step 5 (HXTC #3) will be omitted.

Following the final HXTC infusion in Step 5, participants move into Step 6 for a minimum of
six (6) additional visits: 21, 22, 23, 24, 25, and 26. The 3rd and final leukapheresis will
occur at Visit 23 (Week 21), approximately 9 weeks after the last HXTC infusion to evaluate
the effect of study treatment on IUPM by QVOA.

All participants who receive greater than 8 doses of VOR in the study will be required to
enter a study cancer registry where they will be contacted once a year for 5 years after
completion of their study participation. The registry is created because of genotoxic
findings that were associated with the use of VOR. All participants will be monitored for
development of future malignancies.

Inclusion Criteria:

1. ≥ 18 years and < 65 years of age at screening

2. Ability and willingness of participant to give written informed consent. Note: Due to
the lack of foreseeable benefit to study volunteers, the study will not enroll
illiterate or mentally incompetent volunteers.

3. Karnofsky performance status > 70.

4. Confirmation of HIV-1 infection HIV infection is defined as documentation 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 viral load.

NOTE: The term "licensed" refers to a US FDA-approved kit.

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.

5. On antiretroviral therapy for at least 24 months and on potent antiretroviral therapy
for greater than or equal to 6 months prior to Screening (Visit 1).

Potent ART is defined by current treatment guidelines and consists of at least 2
nucleoside/nucleotide reverse transcriptase inhibitors plus a non-nucleoside reverse
transcriptase inhibitor, integrase inhibitor, or a protease inhibitor without
interruption (defined as missing doses for more than two (2) consecutive days or more
than four (4) cumulative days) in the 24 weeks prior to Screening (Visit 1).

Other potent fully suppressive antiretroviral combinations will be considered on a
case-by-case basis. Prior changes in or elimination of medications for easier dosing
schedule, intolerance, toxicity, or other reasons are permitted if an alternative
suppressive regimen was maintained.

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

7. Able and willing to adhere to protocol therapy, schedule, and is judged adherent to
antiretroviral therapy (adherence defined in inclusion criterion 5.)

8. Plasma HIV-1 RNA < 50 copies/mL at two time points in the previous 12 months prior to
study screening (one time point can be at screening) and never > or equal to 50
copies/mL on two consecutive time points in the last 24 months.

NOTE: A single unconfirmed plasma HIV RNA > or equal to 50 copies/mL but < 1000 c/mL
is allowed if a subsequent assay was < 50 copies/mL; but none in the 6 months
preceding the study screening visit.

9. Plasma HIV-1 RNA < 50 copies/mL at screening (Visit 1).

10. CD4+ cell count ≥ 350 cells/mm3 at screening (Visit 1).

11. No active HCV infection at or within 90 days of screening (Visit 1). Note: No active
HCV defined as negative HCVAb or if HCVAb is positive, reflex HCV RNA is negative.

12. No active HBV infection (measureable HBV DNA or HBVsAg+) at or within 90 days of
screening (Visit 1).

13. Women with written documentation of any of the following:

1. prior hysterectomy OR bilateral oophorectomy (removal of both ovaries)

2. bilateral tubal ligation or non-surgical permanent sterilization

3. Women with intact uterus and ovaries who have not had a period for ≥ one year AND
have a documented FSH level indicating postmenopausal status.

14. All male study volunteers must agree not to participate in a conception process (e.g.
active attempt to impregnate, sperm donation, in vitro fertilization) and, if
participating in sexual activity that could lead to pregnancy, the male study
volunteer and his female partner must use two reliable methods of contraception
(condoms, with or without a spermicidal agent; a diaphragm or cervical cap with
spermicide; an IUD; or hormonal-based contraception) simultaneously while receiving
the protocol-specified study products and for 6 weeks after stopping the study
products. Participants must use a reliable barrier method of contraception (condom,
cervical cap) along with another form of contraception.

NOTE: For female partners who are receiving ritonavir, estrogen-based contraceptives
are not reliable and an alternative method should be suggested.

15. Ability and willingness to provide adequate locator information.

16. Ability and willingness to communicate effectively with study personnel

17. Adequate vascular access for HXTC infusion and leukapheresis.

18. Able to swallow pills without difficulty.

19. Potential participant must have adequate organ function as indicated by the following
laboratory values:

System Laboratory Value Hematological Absolute neutrophil count (ANC) ≥1,500 /mcL Platelets
≥125,000 / mcL Hemoglobin ≥ 12 g/dL (male) and ≥ 11.5 g/dL (females) System Laboratory
Value Coagulation Prothrombin Time (PT) or INR ≤1.1x upper limit of normal (ULN) Chemistry
K+ levels Within normal limits Mg++ levels ≥ 1.4 mEq/L Glucose Screening serum glucose ≤
Grade 1 (fasting or non- fasting) Albumin ≥ 3.5 g/dL or ≥ LLN Renal Creatinine clearance
determined by the CKD-Epi equation found at:
https://www.qxmd.com/calculate/calculator_251/egfr-using-ckd-epi eGFR > 60mL/min Hepatic
Serum total bilirubin Total bilirubin < 1.1 times the ULN range. If total bilirubin is
elevated, direct bilirubin must be < 2 times the ULN range.

NOTE: If participant is on an atazanavir-containing therapy, then a direct bilirubin should
be measured instead of the total bilirubin and must be ≤ 1.0 mg/dL.

AST (SGOT) and ALT (SGPT) < 1.25 X ULN Alkaline Phosphatase < 1.25 X ULN Lipase < 1.1 X ULN
ULN = upper limit of normal LLN = lower limit of normal

Exclusion Criteria:

1. Known allergy or sensitivity to components of VOR and its analog or to components in
the HXTC product.

2. Women without written documentation of menopause (absence of a period for ≥ one year
and FSH level indicating menopause), hysterectomy or bilateral oophorectomy,
non-surgical permanent sterilization, or bilateral tubal ligation.

3. Untreated syphilis infection (defined as a positive rapid plasma reagin (RPR) without
clear documentation of treatment).

Note: In cases of untreated syphilis, participant may re-screen following
documentation of adequate treatment of syphilis

4. All male participants expecting to father children within the projected duration of
the study.

5. Receipt of compounds with HDAC inhibitor-like activity, such as valproic acid within
30 days prior to screening.

6. Use of any investigational antiretroviral agents within 30 days prior to screening
(Visit 1).

7. If the study PI (or designee) or protocol team is unable to construct a fully active
alternative cART regimen based on previous resistance testing and/or treatment
history.

8. Use of the following medications that carry risk of torsade des pointes: amiodarone,
arsenic trioxide, astemizole, bepridil, chloroquine, chlorpromazine, cisapride,
clarithromycin, disopyramide, dofetilide, domperidone, droperidol, erythromycin,
halofantrine, haloperidol, ibutilide, levomethadyl, mesoridazine, methadone,
pentamidine, pimozide, probucol, procainamide, quinidine, sotalol, sparfloxacin,
terfenadine, thioridazine.

9. Use of any of the following within 90 days prior to screening (Visit 1):
immunomodulatory, cytokine, or growth stimulating factors such as systemic
corticosteroids, cyclosporine, methotrexate, azathioprine, anti-CD25 antibody, IFN,
interleukin-2 (IL-2), coumadin, warfarin, or other Coumadin derivative anticoagulants.

10. Prior use of any HIV immunotherapy or HIV vaccine within 12 months prior to Screening
(Visit 1), except for prior HXTC infusions.

11. Received any infusion blood product, immune globulin, or hematopoietic growth factors
within 90 days prior to study screening (Visit 1).

12. Pregnancy or breast-feeding.

13. History or other clinical evidence of severe illness, malignancy, immunodeficiency
other than HIV, or any other condition that would make the participant unsuitable for
the study in the opinion of the investigator (or designee).

14. Use of topical steroids over a total area exceeding 0.5mg/kg/day within 30 days prior
to Screening (Visit 1).

15. Treatment for an active AIDS-defining opportunistic infection within 90 days prior to
Screening (Visit 1).

16. Any active malignancy that may require chemotherapy or radiation therapy.

17. Compulsorily detained (involuntarily incarcerated) for treatment of either a
psychiatric illness or a physical illness, e.g., infectious disease. Prisoner
recruitment and participation is not permitted.

18. Known psychiatric or substance abuse disorders that would interfere with participant's
ability to fully cooperate with the requirements of the trial as assessed by the study
investigator (or designee).

19. History or other clinical evidence, as assessed by the study PI (or designee), of
significant or unstable cardiac disease (e.g., angina, congestive heart failure,
recent myocardial infarction, significant arrhythmia) or clinically significant
electrocardiogram (ECG) abnormalities. Any history of cardiac rhythm disturbance
requiring medical or surgical therapy.

20. Unable to have a person available to drive participant home at infusion visits.

21. Participation in another investigational clinical research study (with the exception
of an antiretroviral treatment trial that uses FDA approved antiretroviral agents) or
use of investigational agents within 30 days prior to screening (Visit 1).

NOTE: Co-enrollment in observational only studies is permitted.

NOTE: Co-enrollment in the ACTG 5332 REPRIEVE study (NCT023442900) and using FDA approved
pitavastatin is permitted provided participant enrolled on ACTG 5332 and has taken the
study provided medication ≥ 4 months.