Angiotensin Receptors and Age Related Mitochondrial Decline in HIV Patients

HIV related premature cellular aging and declines in mitochondrial function are closely
linked. Dysfunctional mitochondria generate higher levels of reactive oxygen species (ROS)
and provide less ATP supply cellular energy. Impaired turnover of damaged mitochondria leads
to gradual but progressive decline in energy metabolism, increases in muscle fibrosis and
clinically apparent weakness. The Renin Angiotensin System (RAS) is a central hormonal system
that contributes to mitochondrial dysfunction and impacts both lifespan and function across
multiple organ systems. Deletion of the angiotensin type 1 receptor (AT1R) results in a
25-30% extension of lifespan in mouse models, partly through increasing mitochondrial
numbers. Blocking of AT1R reduces a number of age-related morbidities in mice, and in human
studies. A plethora of data implicates RAS modulation in marked effects on fitness, frailty
and beneficial responses to exercise in older adults. Despite this, there are virtually no
data examining RAS biology in HIV+ vs. age-matched HIVsubjects, no data of RAS in relation to
key HIV-specific variables (duration of HIV, treatment history, immune markers), and no data
examining the effects of blocking AT1R on physical function in HIV infected subjects. In this
study, we will examine the RAS and its contribution to premature mitochondrial failure in HIV
patients. We will begin to fill this void by enrolling 40 HIV+ subjects in a randomized,
double-blinded, placebo controlled pilot study of treatment with AT1R blocker to determine
the feasibility of a larger trial, estimate effect size, assess the correlation of
angiotensin receptor (AR) expression in peripheral blood cells and muscle cells, and the
association of AR expression with physical function measures and immunity.

Inclusion Criteria:

- able to provide informed consent

- able to attend an extended (~4 hour) Clinical Research Visit

- documented HIV seropositivity

- on a stable anti-retroviral therapy (ART) regimen for at least 12 months

- HIV plasma viral load < 50 copies/ml for at least 6 months

- Systolic blood pressure >110

Exclusion Criteria:

- creatinine > 1.5 ULN (or creatinine clearance < 60 ml/min)

- anti-hypertensive therapy with ACE-I or AT1R-blockers

- inability to perform functional measures (e.g. non-ambulatory without assistance,
requires a prosthesis)

- recent (within 30 days) acute illness requiring medical therapy or hospitalization

- immunosuppressive agents (e.g. > 20 mg/d x 2 or more weeks of prednisone or
equivalent, chemotherapy) in the last 6 months

- cancer requiring treatment w/in 3 yrs (except for non-melanoma skin cancer)

- blood thinning medications such as Coumadin or Plavix or a bleeding disorder such as
hemophilia that could cause complications during muscle biopsies

- pregnancy (will provide urine test for females of child bearing potential)

- regular use of non-steroidal anti-inflammatory drugs or other immune modulating
agents.