Retrotransposition and senescence in mouse heart tissue by viral protein R of human immunodeficiency virus-1.

Combination antiretroviral therapy (cART) has greatly improved the prognosis of patients with human immunodeficiency virus type-1 (HIV-1) infection. However, cardiovascular disease (CVD) remains a serious issue even in the post-cART era. Viral protein R (Vpr), an accessory gene product of HIV-1, exerts pleiotropic activities such as the induction of DNA damage signals, apoptosis by mitochondrial membrane depolarization, G2/M-phase cell cycle abnormalities, and retrotransposition. Importantly, some of these cellular responses are induced by the trans-acting activity of Vpr. Recently, we established an enzyme-linked immunosorbent assay to detect Vpr and reported that about 22% of blood samples from 100 HIV-1-positive patients were positive for Vpr. Here, we investigated the biological effects of recombinant Vpr (rVpr) in vivo. We observed that repeated injections of rVpr increased the copy number of long interspersed element-1 (L1) in the heart genome in mice. rVpr also increased the number of cells positive for senescence-associated β-galactosidase (SA-β-gal) and fibrosis in the heart. Notably, co-administration of a reverse transcriptase inhibitor reduced the number of rVpr-induced SA-β-gal-positive cells and fibrosis concomitantly with the attenuation of L1 retrotransposition. Interestingly, a Vpr mutant defective for mitochondrial dysfunction also induced heart senescence and increased L1 copy number. Together with a recent report that L1 retrotransposition functions as a molecular basis of senescence, our current data suggest that rVpr-induced L1 retrotransposition is linked with senescence in heart tissue. We would propose that Vpr in the bloodstream may be one of risk factors for CVD, and that its monitoring will lead to well understanding of the heterogeneity and multifactorial mechanisms of CVD in HIV-1 patients.
Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest
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