Osteopontin is an integral pro‐fibrotic mediator of myocardial fibrosis in HIV infection.

Abstract

With introduction of antiretroviral therapy (ART), human immunodeficiency virus (HIV) has transitioned to a chronic, progressive inflammatory disease, with increasing evidence of subclinical and early‐onset cardiovascular comorbidities. PWH have a greater risk and prevalence of diastolic dysfunction compared to seronegative individuals. In a clinical cohort of ART‐adherent, virally suppressed women with HIV, we showed women with HIV exhibited increased myocardial extracellular volume and reduced diastolic strain rate compared to matched seronegative women. Taken together, we hypothesize that chronic HIV infection promotes a pro‐fibrotic environment in the heart, perturbing ventricular homeostatic function. First, we utilized the highly translatable simian immunodeficiency virus (SIV)‐infected rhesus macaque model. We used three cohorts in our study: uninfected animals (SIV‐), SIV‐infected untreated animals (SIV+), and SIV‐infected animals receiving a clinically relevant ART regimen (SIV+ART). Assessing fibrosis in the left ventricle, we observed greater interstitial fibrosis in SIV+ animals compared to SIV‐ and SIV+ART animals. We identified osteopontin as a potential fibrotic signal in the heart from its role in macrophage function, as a matricellular protein, and as an immunomodulatory cytokine. We observed significant differences in post‐translational enzymatic processing of osteopontin between the three groups, and SIV+ animals showed a significant increase in full‐length osteopontin compared to SIV‐ and SIV+ART. Lastly, we used an HIV‐infected humanized mouse model to functionally inhibit osteopontin in vivo with an RNA aptamer. HIV‐infected mice exhibited greater fibrotic burden in the left ventricle of the heart compared to uninfected controls. HIV‐infected mice treated with an osteopontin‐inhibiting RNA aptamer had reduced fibrotic content in the left ventricle compared to HIV infected mice, showing similar levels to uninfected mice. Together, these data suggest that osteopontin is an integral fibrotic signal in the heart and a potential adjunctive target in reducing HIV‐associated myocardial fibrosis.