Researching Alveolar Macrophage Improvements With Supplements in HIV

This new proposal entitled "The alveolar macrophage pool is a reservoir of HIV" addresses a
fundamental question; specifically, does the alveolar macrophage pool serve as a reservoir of
HIV even when peripheral viral suppression is achieved by anti-retroviral therapy (ART) and
if so, how does this reservoir alter the environment within the alveolar space and impair
alveolar macrophage immune function? This is a critical question to address as lung
infections remain the leading cause of death in persons living with HIV even when they are
adherent to ART. There is compelling experimental evidence that HIV infection inhibits
anti-oxidant defenses within the alveolar space and causes severe redox stress. Based on
preliminary data presented in this proposal, the investigators hypothesize that HIV inhibits
the expression and actions of Nrf2, the master transcription factor that activates the
anti-oxidant response element (ARE), in part by inducing zinc deficiency in this vulnerable
microenvironment, and thereby prevents the alveolar epithelium and the alveolar macrophage
from generating glutathione and other anti-oxidants that are critically required to maintain
a healthy redox potential within the alveolar space. The investigators further hypothesize
that as a result of this targeted inhibition of the Nrf2-ARE signaling pathway, HIV promotes
its own ability to infect alveolar macrophages and accumulate a large pool of intracellular
pro-virus that produces a large HIV reservoir within the alveolar space. In parallel,
HIV-induced oxidative stress shifts the alveolar macrophage toward alternative activation (so
called 'M2 phenotype'). As a consequence, the innate immune capacity of the alveolar
macrophage is impaired and this not only confers further resistance to clearing the viral
reservoir but also renders the infected individual susceptible to serious lung infections.
The investigators will leverage ongoing collaborative clinical studies in HIV-infected
individuals. As a result, investigators not only have ongoing access to alveolar epithelial
lining fluid and macrophages from well-defined subsets of HIV-infected individuals, they also
have the expertise to apply state-of-the-art basic techniques in HIV pathogenesis,
metabolomics, and redox signaling to test hypotheses. In parallel, the investigators are
already conducting a prospective clinical trial of dietary zinc and S-adenosylmethionine (a
thiol anti-oxidant that among its many actions increases the glutathione pool in the alveolar
space) in HIV-infected individuals with inadequate immunological responses to ART
(NCT01806870). This unique cohort will form the foundation for a greatly expanded clinical
trial that will allow the investigators to test the corollary hypothesis that therapeutic
strategies designed to improve zinc bioavailability and the redox potential within the
alveolar space can enhance alveolar macrophage innate immune function and significantly
decrease the HIV reservoir in the lung. This project will produce novel insights into how we
can target the alveolar macrophage pool to decrease HIV burden as well as improve lung health
in these vulnerable individuals.

Inclusion Criteria:

- Subjects living with HIV-1 infection who have been on anti-retroviral therapy (ART)
for a minimum of 18 months and are followed longitudinally for their HIV healthcare in
one of the study sites in Atlanta.

- Ability to give informed consent.

Exclusion Criteria:

- Documented history of cirrhosis or a direct bilirubin ≥ 2.0 mg/ld.

- Documentation of left ventricular ejection fraction < 40% or myocardial infarction
within the past 6 months.

- End-stage renal disease requiring dialysis or a serum creatinine ≥ 2 mg/dL.

- Spirometry with Forced vital capacity (FVC) or Forced expiratory volume in 1 second
(FEV1) < 70% of predicted value.

- Diabetes

- Known or possible pregnancy or attempting to become pregnant or breastfeeding

- BMI < 17

- Age < 21

- Parkinson's disease: these are all b/c the SAMe risks sections states that these pts
will not qualify

- Bipolar disorder

- Bleeding disorders such as thrombocytopenia or significant gastrointestinal bleeding
within the past year