HIV‐1 triggers apoptosis in primary osteoblasts and HOBIT cells through TNFα activation

Abstract

Several HIV-1 infected patients show bone loss and osteopenia/osteoporosis during the course of disease. The mechanisms underlying this degenerative process are largely unsettled and it has not been determined yet whether bone dysfunction is linked to HIV-1-mediated direct and/or indirect effects on osteoblasts/osteoclasts cross-talk regulation. This study investigated the effects of HIV-1(IIIb) and HIV-1(ADA) strains on osteoblasts using the osteoblast-derived cell line (HOBIT) and primary human osteoblasts as cellular models. The challenge of these cell cultures by both HIV-1 strains triggered a significant apoptosis activation unrelated to viral infection, since proviral HIV-1 DNA and supernatant HIV-1 RNA were not detected by real time PCR or b-DNA assays respectively. Under the experimental conditions, even heat-inactivated HIV-1 or cross-linked recombinant gp120 treatment of HOBIT and osteoblasts induced programmed cell death, suggesting that apoptosis is regulated by the interaction between HIV-1 gp120 and cell membrane. The analysis of cell culture supernatants showed a significant up-regulation of TNFalpha, a pleiotropic protein considered an apoptosis inducer in the osteoblast model. In fact, pretreatment of HOBIT and osteoblast cell cultures with anti-TNFalpha polyclonal antibody tackled effectively HIV-1 related induction of cell apoptosis. As a whole, these results indicate that HIV-1 may impair bone mass structure homeostasis by TNFalpha regulated osteoblast apoptosis.

Bone Changes and Fracture Risk in Individuals Infected With HIV

“…In vitro exposure of osteoblast cells to HIV-1 activated apoptosis of osteoblast cells [22]. However, the apoptosis was inhibited when the osteoblast cells were treated with anti-TNF-α, suggesting a role for TNF-α in HIV-1-induced bone disease [22].…”

“…IL-1 and TNF-α may inhibit osteoblast function [14,18,19], whereas IL-1, IL-6, IL-11, and TNF-α have been found to stimulate osteoclasts [14,20,21]. In vitro exposure of osteoblast cells to HIV-1 activated apoptosis of osteoblast cells [22]. However, the apoptosis was inhibited when the osteoblast cells were treated with anti-TNF-α, suggesting a role for TNF-α in HIV-1-induced bone disease [22].…”

HIV and Bone Loss

“…Interestingly, HIV-1 does not directly infect osteoblasts [37]. Rather, there is growing evidence that the envelope protein gp120 interacts with the osteoblast cell membrane receptor and causes apoptosis, possibly through cytokine alterations such as tumor necrosis factor-α (see Fig.…”

Bone Metabolism and HIV Infection

“…A number of studies suggest HIV proteins can shift the OPG/RANKL ratio in favour of RANKL-mediated osteoclastic activation (40). HIV Vpr (viral protein R), a factor needed for viral replication being required for the nuclear import of the HIV-1 pre-integration complex, up-regulates RANKL, potentiating glucocorticoid-induced stimulation of RANKL (41). gp120 also stimulates RANKL (42).…”