This study will test the safety and effectiveness of genetically altered T lymphocytes
(white blood cells of the immune system) in reducing viral load in patients infected with
the human immunodeficiency virus (HIV). The lymphocytes will have two genes inserted into
them; a laboratory-manufactured anti-HIV gene designed to inhibit HIV reproduction (either
the RevTD or Rev-TD-antiTAR gene), and a "marker" gene that will show whether or not the
inserted genes have gotten into the cells.
Identical twin pairs 18 years of age and older- one of whom is HIV-positive (infected with
the human immunodeficiency virus) and the other HIV-negative (not infected) may be eligible
for this study.
All participants will have a complete medical history and physical examination, blood tests
and a tetanus booster shot, if indicated. The non HIV-infected twin will then undergo
lymphapheresis to collect lymphocytes. In this procedure, whole blood is collected through
a needle placed in an arm vein. The blood circulates through a machine that separates it
into its components. The lymphocytes are then removed, and the red cells and plasma are
returned to the donor, either through the same needle or through a second needle placed in
the other arm.
The donor cells are grown in the laboratory for a few days, and then the new genes are
inserted into them. The genetically altered cells are grown in the laboratory for several
days until their numbers increase approximately a thousand-fold. They are then infused
intravenously (through a vein) into the infected twin. These procedures-lymphapheresis,
gene modification and infusion-will be repeated at approximately 2-month intervals up to
Each lymphocyte infusion takes about 60 minutes. The patient's vital signs (temperature,
pulse, blood pressure and breathing) are monitored frequently during the infusion and hourly
for 4 hours after the infusion. Blood samples are taken the day of the infusion, 3 days
later, and then weekly to monitor the gene-modified cells, immune status, viral activity,
and other factors. These tests may be done less often as the study progresses and more is
learned about the safety of the infusions. The infusions are done on an outpatient basis
unless side effects require that they be done in the hospital with post-infusion monitoring
for at least 24 hours.
Patients will be followed for long-term effects of treatment monthly for the first 3 months,
once a month for the next 9 months and yearly from then on.
This study will contribute information about the use and side effects of gene therapy in HIV
infection that may lead to new treatment strategies. A potential direct benefit to
HIV-infected individuals participating in this study is reduced viral load; in laboratory
studies, the RevTD and Rev-TD-antiTAR genes have inhibited HIV spread in the test tube.
However, this is an early phase of study, and the likelihood of receiving this benefit is
This phase I/II pilot study will evaluate the safety, relative survival, and potential
efficacy of infusions of activated, genetically engineered, syngeneic CD4+ T lymphocytes
obtained from HIV-1 seronegative identical twins. T cells from each seronegative twin will
be obtained by apheresis, enriched for CD4+ cells, induced to polyclonal proliferation with
anti-CD3 and rIL-2 stimulation, divided into aliquots which will then be individually
transduced with a control retroviral vector and up to two additional retroviral vectors
containing potentially therapeutic genes (antisense TAR and/or transdominant Rev). These
engineered T cell populations will be expanded 10-1,000 fold in numbers during 1-2 weeks of
culture, and then will be infused into the seropositive twins. The relative survival of the
uniquely engineered T cell populations will be monitored by vector-specific PCR, while the
recipients' functional immune status is monitored by standard in vitro and in vivo testing
protocols. A total of up to 4 cycles of treatment may be given using identical or different
combinations of control and anti-HIV-1 retroviral vectors.
- An identical twin pair, one of whom is seropositive for HIV-1, the other twin
seronegative, by standard ELISA and Western blot testing.
- Patients with Kaposi's sarcoma limited to the skin and/or mucous membranes are
eligible for this study, but must not have received any systemic therapy for
- KS within 4 weeks prior to entry. The diagnosis of KS must have been confirmed by
- Free from serious psychological or emotional illness and able to provide written
- Anticipated survival greater than 3 months.
- 18 years of age or older.
- Treatment with FDA-approved and/or expanded access antiretroviral agent(s) for
patients with baseline CD4 counts below 500 cells/mm(3). Patients with baseline CD4
counts above 500 cells/mm(3) are eligible to receive cell therapy on this protocol,
but must be treated with antiretroviral therapy if evidence of significant and
persistent viral activation occurs in association with a cell infusion. "Significant
and persistent viral activation" is defined as a 50 percent or greater increase above
baseline in any virologic parameter for at least 2 consecutive weeks.
- Recipient's CD4 count greater than 50 cells/mm(3).
- Recipient and Donor willing to have samples stored and undergo HLA testing.
EXCLUSION CRITERIA (Donor and Recipient):
- Unwillingness to comply with current NIH Clinical Center guidelines concerning
appropriate notification of all current sexual partners of an individual regarding
his or her HIV-1 positive sero-status and the risk of transmission of HIV-1
- Recent history of substance abuse unless evidence is provided of an ongoing
therapeutic intervention (i.e. medical therapy or counseling) to control such abuse.
- Pregnant at entry or unwillingness to practice barrier birth control or abstinence
during the study.
- No experimental therapy within 4 weeks of study participation. Antiretroviral agents
available on an FDA-sanctioned, expanded access basis are permitted.
EXCLUSION CRITERIA (Donor):
- Untreated or inadequately treated medical condition (e.g., cardiopulmonary disease,
acute infection) which, in the judgement of the Principal Investigator, precludes
- Serologic positivity for Epstein Barr virus, Cytomegalovirus, Hepatitis B or
Hepatitis C, if and only if the recipient twin tests seronegative for the