Leukapheresis to Obtain Plasma or Lymphocytes for Studies of HIV-infected Patients, Including Long-term Non-progressors

In an attempt to elucidate the mechanism(s) of immune-mediated restriction of HIV viral
replication, we aim to study four groups of individuals: 1) HIV-infected long-term
nonprogressors (LTNP), who appear to control HIV primarily through virus-specific cellular
immunity; 2) HIV-infected patients who have broadly cross neutralizing antibody activity
against HIV; 3) HIV-infected patients receiving antiretroviral therapy who will undergo a
treatment interruption; and 4) the family members of patients exhibiting immunologic control
of HIV infection. Although most of our previous efforts have focused on investigating the
virus-specific immune responses in a unique group of patients termed LTNP who control HIV by
cellular immune-mediated mechanisms, more recently, another group of rare individuals who
naturally develop broadly cross neutralizing antibody activity against HIV isolates have also
been identified in our laboratory. Passive transfer studies in nonhuman primates have
demonstrated that neutralizing antibodies detectable in a subject at the time of challenge
can protect from infection. We aim to recruit more of these patients in an effort to further
characterize and compare their virus-specific cellular and humoral immune responses with
those in individuals experiencing progressive infection. In addition, it is necessary to
define whether putative correlates of immune mediated restriction of viral replication are a
cause or an effect of HIV viremia. To this end, we are enrolling patients who will be
discontinuing their antiretroviral regimen and examine virologic and immunologic parameters
during the treatment interruption. Through this arm of the study, we will attempt to further
characterize the mechanisms by which HIV evades and/or suppresses an effective anti-viral
immune response and to identify features of the virus or the patients immune responses that
are associated with virologic control following treatment interruption. As we attain greater
insight into differences between these patient groups, we hope to perform genetic studies
that would enable us to more precisely identify susceptibility or protective genes, which
could be potentially used to construct a familial pedigree. We anticipate that all of these
findings will contribute to an enhanced understanding of the nature of effective HIV-specific
humoral and cellular immunity, which will help focus future vaccine design efforts. For our
studies, it will be necessary to obtain larger quantities of plasma or mononuclear cells than
can be safely obtained by simple phlebotomy. These components can be easily and safely
obtained using apheresis procedures in the Clinical Center Apheresis Unit. This protocol is
designed to conform to the requirements of the Apheresis Unit for donors to have
leukapheresis or plasmapheresis procedures.

- INCLUSION CRITERIA FOR PATIENTS NOT INCLUDED UNDER THE TREATMENT INTERRUPTION ARM:

1. Adult (18 years old or older).

2. Eligibility to undergo apheresis procedures; or for patients who are unable to
undergo apheresis, willingness to undergo blood draw for research purposes that
remain within safety guidelines established by NIH policy.

3. Willingness to give informed consent for the storage of blood or

tissue samples and HLA testing.

4. AND at least one of the following:

- An HIV-seropositive patient categorized as an LTNP as defined by clinical
and laboratory criteria, regardless of HLA class I type.

- HIV-seropositive HLA B*27+, B*35+, B*44+, B*57+, B*58+ and/or A*02+
progressors.

- HIV-seropositive patients possessing sera with broadly cross-neutralizing
antibody activity to HIV.

- Persons who are seronegative for HIV but are family members of seropositive
patients exhibiting immunologic control of HIV.

EXCLUSION CRITERIA FOR PATIENTS NOT INCLUDED UNDER THE TREATMENT INTERRUPTION ARM:

1. Pregnant women.

2. Cardiovascular instability, severe anemia, inadequate venous access, severe
coagulation disorder or any other condition that the Principal Investigator or
Apheresis Unit staff considers a contraindication to the apheresis procedure or
research blood draw.

INCLUSION CRITERIA FOR PATIENTS CONSENTING TO UNDERGO A TREATMENT INTERRUPTION:

1. Subjects greater than or equal to 18 years of age.

2. HIV infection confirmed by ELISA and Western blot.

3. Ability to sign informed consent and willingness to comply with study requirements and
clinic policies.

4. In the judgment of the PI, patient has satisfactory knowledge of the benefits of
continuing ART as well as the risks of discontinuing such treatment. The patient has a
private physician and the decision to interrupt antiretroviral therapy, the target
point (i.e. viral load or CD4+ T cell count) to reinitiate therapy, and the regimen of
antiretrovirals used upon re-initiation of therapy will be made with this private
physician.

5. History of at least 2 months of ongoing ART, defined as a minimum three drug regimen
consisting of at least two nucleoside analogs and one or two protease inhibitors or
one non-nucleoside reverse transcriptase inhibitor (NNRTI) or classesone integrase
inhibitor OR patients that are currently off therapy who are planning on resuming or
initiating a ART regimen within the next 3 months.

6. No baseline CD4+ T cell counts less than or equal to 500 cells/micro liters, with
confirmation, within the last 3 months.

7. Asymptomatic for significant HIV-related illnesses, such as opportunistic infections
and malignancies other than mucocutaneous Kaposi s sarcoma.

8. For patients on IL-2 therapy, agreement to resume ART while undergoing treatment
cycles.

9. Eligibility to undergo apheresis procedures.

EXCLUSION CRITERIA FOR PATIENTS CONSENTING TO UNDERGO A TREATMENT INTERRUPTION:

1. Psychiatric illness that, in the opinion of the PI, might interfere with study
compliance.

2. Active substance abuse or history of prior substance abuse that may interfere with
protocol compliance or compromise patient safety.

3. Women who are pregnant or breastfeeding.

4. Creatinine greater than 2 mg/dL.

5. Platelet count less than 100,000/mm(3), hemoglobin less than 9 mg/dL, neutrophils less
than 750/mm(3).

6. PT or PTT (in the absence of documented anti-cardiolipin antibody) prolonged by
greater than 2 seconds.

7. Known underlying bleeding disorder that would preclude leukapheresis.

8. Significant cardiac, pulmonary, kidney, rheumatologic, gastrointestinal, or CNS
disease as detectable on routine history, physical examination, or screening
laboratory studies.

9. Documented history of virologic relapse in the past year following interruption of ART
therapy.

10. History of significant opportunistic infection or HIV-associated malignancy.

11. Patient must not ever have had a total CD4 count of less than or equal to 150
cells/cubic millimeter during the year prior to enrollment. At least 2 measurements,
possibly including the measurement during the screening visit and/or H&P visit, must
be available.

12. Due to a possible increased risk of a hypersensitivity reaction, patients on an
abacavir-containing regimen will not be eligible for treatment interruption.

13. Patients with chronic hepatitis B infection requiring receiving treatment with 3TC
(lamivudine), adefovir or tenofovir for suppression are not eligible for this study.

14. Cardiovascular instability, severe anemia, inadequate venous access, severe
coagulation disorder or any other condition that the Principal Investigator or
Apheresis Unit staff considers a contraindication to the apheresis procedure or
research blood draw.