The HIV proteins Tat and Nef promote human bone marrow mesenchymal stem cell senescence and alter osteoblastic differentiation
Open accessAbstract
To maintain bone mass turnover and bone mineral density (BMD), bone marrow (BM) mesenchymal stem cells (MSCs) are constantly recruited and subsequently differentiated into osteoblasts. HIV-infected patients present lower BMD than non-HIV infected individuals and a higher prevalence of osteopenia/osteoporosis. In antiretroviral treatment (ART)-naive patients, encoded HIV proteins represent pathogenic candidates. They are released by infected cells within BM and can impact on neighbouring cells. In this study, we tested whether HIV proteins Tat and/or Nef could induce senescence of human BM-MSCs and reduce their capacity to differentiate into osteoblasts. When compared to nontreated cells, MSCs chronically treated with Tat and/or Nef up to 30 days reduced their proliferative activity and underwent early senescence, associated with increased oxidative stress and mitochondrial dysfunction. The antioxidant molecule N-acetyl- cysteine had no or minimal effects on Tat- or Nef-induced senescence. Tat but not Nef induced an early increase in NF-κB activity and cytokine/chemokine secretion. Tat-induced effects were prevented by the NF-κB inhibitor parthenolide, indicating that Tat triggered senescence via NF-κB activation leading to oxidative stress. Otherwise, Nef- but not Tat-treated cells displayed early inhibition of autophagy. Rapamycin, an autophagy inducer, reversed Nef-induced senescence and oxidative stress. Moreover, Tat+Nef had cumulative effects. Finally, Tat and/or Nef decreased the MSC potential of osteoblastic differentiation. In conclusion, our in vitro data show that Tat and Nef could reduce the number of available precursors by inducing MSC senescence, through either enhanced inflammation or reduced autophagy. These results offer new insights into the pathophysiological mechanisms of decreased BMD in HIV-infected patients.
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HIV proteins Tat and Nef and protease inhibitors lopinavir and atazanavir are capable of inducing senescence in BM-MSCs.
“These conflicts are possibly reconciled by reports that find both HIV proteins Tat and Nef and protease inhibitors lopinavir and atazanavir are capable of inducing senescence in BM‐MSCs.”
From The struggle of a good friend getting old: cellular senescence in viral responses and therapy (2021) · cites this paper as Beaupere et al, 2015
Senescent BM-MSCs do not effectively differentiate into osteoblasts and deposit reduced calcium in vitro.
“Importantly, senescent BM‐MSCs do not be effectively differentiated into osteoblasts and deposit reduced levels of calcium in vitro (Hernandez‐Vallejo et al, 2013; Beaupere et al, 2015).”
From The struggle of a good friend getting old: cellular senescence in viral responses and therapy (2021) · cites this paper as Beaupere et al, 2015
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- Authors
- Beaupere, C., Garcia, M., Larghero, J., Fève, B., Capeau, J., & Lagathu, C.
- Affiliations
- Sorbonne Universités; UPMC Univ Paris 06; UMR_S 938; CDR Saint-Antoine F-75012 Paris France
- Inserm (FR)
- Inserm; UMR1160; Institut Universitaire d'Hématologie; Hôpital Saint-Louis; 75010 Paris France
- Corresponding author
- Lagathu, Claire
- Venue
- Aging Cell
- Publisher
- Wiley
- Published
- 2015-04-07
- Volume
- 14
- Issue
- 4
- Pages
- 534-546
- ISSN
- 1474-9718 (ISSN-L)
- PMC
- PMC4531068
- OpenAlex
- W1974475104
- Cited by
- 85
- References
- 42
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 8 · 2023: 7 · 2022: 7 · 2021: 7 · 2020: 14 · 2019: 9 · 2018: 4 · 2017: 11 · 2016: 7 · 2015: 1
- FWCI
- 7.44
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Aging Cell (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- Funders
- Institut National de la Santé et de la Recherche Médicale
- Topics
- Health Sciences › Medicine › Emergency Medicine › HIV-related health complications and treatments
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Keywords
- HIV-1 Tat protein, HIV Nef protein, bone marrow mesenchymal stem cells, cellular senescence, osteogenic differentiation, bone mineral density, osteoporosis, oxidative stress, mitochondrial dysfunction, NF-κB signaling, autophagy, parthenolide, rapamycin, HIV-associated bone loss, people living with HIV
- MeSH terms
- Acetylcysteine, Antioxidants, Autophagy, Bone Marrow Cells, Cell Differentiation, Gene Expression Regulation, Humans, Mitochondria, Osteoblasts, Recombinant Proteins, Sesquiterpenes, Signal Transduction, Osteocalcin, Interleukin-6, Interleukin-8, NF-kappa B, Cellular Senescence, Oxidative Stress, Sirolimus, Cell Proliferation, nef Gene Products, Human Immunodeficiency Virus, tat Gene Products, Human Immunodeficiency Virus, Mesenchymal Stem Cells, Primary Cell Culture
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