In the United States, HIV infection has become a chronic disease with increasing evidence for an accelerated aging phenotype. By 2015, over half of HIV-infected individuals will be 50 years old or older. Notably, chronic HIV infection is associated with persistent inflammation, fibrosis and increased risk for frailty - conditions associated with muscl aging. We propose that persistent inflammation in chronic HIV infection promotes accelerated muscle fibrosis, which is then predicted to accelerate functional impairment, leading to a premature aging phenotype. We suggest that chronic inflammation promotes an imbalance in muscle tissue remodeling resulting in an accelerated, and potentially subclinical muscle fibrosis that is likely to limit physical function in the long term as the HIV population ages. We will recrit a cohort of at risk HIV-infected adults on stable ART and demographically matched uninfected adults to evaluate the following three specific aims: 1. Determine whether inflammation is related to skeletal muscle fibrosis in adults on effective ART. 2. Determine whether skeletal muscle fibrosis is related to physical function. 3. Characterize potential synergy between the fibrotic TGF?1 pathway and inflammatory pathway, and characterize the novel inflammatory inhibitor JQ1, the inflammatory inhibitor Rosiglitazone, and the fibrotic inhibitor Losartan. If fibrosis is confirmed in this study and there is evidence of activated TGF?1 signaling, these patients could be treated with anti-fibrotic agents such as Losartan, a Food and Drug Administration-approved drug with potent anti-fibrotic properties in skeletal muscle.

Public Health Relevance

Despite the considerable success of highly active anti-retroviral therapy (HAART), individuals chronically infected with HIV remain at higher risk for declines in musculoskeletal function and increased frailty. We will test a model wherein HIV associated chronic inflammation promote an imbalance in muscle tissue remodeling resulting in an accelerated muscle fibrosis. We expect that skeletal muscle fibrosis would help to explain the observed disproportionate decline in muscle function, a phenomenon that is similar to what is observed in human aging.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI108541-01A1
Application #
8797174
Study Section
Special Emphasis Panel (ZRG1-AARR-K (58))
Program Officer
Sharp, Gerald B
Project Start
2014-06-01
Project End
2019-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
$830,350
Indirect Cost
$331,295
Name
Boston Medical Center
Department
Type
DUNS #
005492160
City
Boston
State
MA
Country
United States
Zip Code
02118