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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-AARR-K (58))
Program Officer
Sharp, Gerald B
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Boston Medical Center
United States
Zip Code
Tran, Thanh; Guardigni, Viola; Pencina, Karol M et al. (2018) Atypical Skeletal Muscle Profiles in Human Immunodeficiency Virus-Infected Asymptomatic Middle-Aged Adults. Clin Infect Dis 66:1918-1927
Sebastiani, Paola; Thyagarajan, Bharat; Sun, Fangui et al. (2017) Biomarker signatures of aging. Aging Cell 16:329-338
Guo, Wen; Pencina, Karol M; O'Connell, Karyn et al. (2017) Administration of an activin receptor IIB ligand trap protects male juvenile rhesus macaques from simian immunodeficiency virus-associated bone loss. Bone 97:209-215
Sebastiani, Paola; Thyagarajan, Bharat; Sun, Fangui et al. (2016) Age and Sex Distributions of Age-Related Biomarker Values in Healthy Older Adults from the Long Life Family Study. J Am Geriatr Soc 64:e189-e194