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HIV-1 gp160 protein-macrophage interactions modulate mesangial cell proliferation and matrix synthesis
P C Singhal1, P Sharma, P Garg
1Department of Medicine, Long Island Jewish Medical Center, New Hyde Park, NY 11042, USA.
Abstract:
Patients with HIV infection often develop glomerular lesions (focal segmental glomerular sclerosis). Because mesangial expansion (enhanced mesangial cell (MC) growth and matrix accumulation) has been demonstrated to precede the development of focal segmental glomerulosclerosis, we studied the effect of the interaction between HIV-1 proteins such as gp160 envelope protein and macrophages on mesangial cell proliferation and matrix synthesis. We determined the effect of control media, serum-free macrophage supernatant (MSP), and serum-free HIV-1 gp 160 protein-treated MSP (gp 160-MSP) on the proliferation of MC and synthesis of collagen type IV (a component of mesangial matrix). MSP (20%) enhanced (P < 0.01) MC proliferation (control, 7.58 +/- 0.29 versus MSP, 9.06 +/- 0.25 x 10(4) cells/ml), whereas gp 160-MSP (20%) inhibited (P < 0.001) MC proliferation (gp160-MSP, 5.58 +/- 0.14 x 10(4) cells/ml). gp160-MSP modulated MC proliferation in a dose-dependent manner; it enhanced cell proliferation at a lower concentration but inhibited cell proliferation at a higher concentration. Anti-TGF-beta antibody attenuated the effect of gp160-MSP on MC proliferation at lower as well as higher concentrations. Bromodeoxyuridine incorporation studies also showed the modulation of MC proliferation by gp160-MSP. Interaction of other HIV proteins such as HIV-1 Gag4 and HIV-1 Tat with macrophages did not affect MC proliferation when compared with MSP alone. gp160-MSP also enhanced (P < 0.001) synthesis of type IV collagen by MC (control, 467.8 +/- 9.0; MSP, 501.0 +/- 25.0; gp160-MSP, 775.5 +/- 39.0 ng/mg protein). The effect of gp160-MSP on collagen synthesis by MC was dose-dependent. Anti-TGF-beta antibody attenuated the gp160-MSP-induced mesangial cell collagen synthesis. The present study provides a basis for speculation that macrophage-gp160 interaction products have the potential to cause expansion of the mesangium.
Insights
HIV-1 gp160 protein interacting with macrophages influences mesangial cell (MC) proliferation and collagen synthesis. This interaction, mediated by TGF-beta, may contribute to HIV-associated kidney disease by causing mesangial expansion.
Area of Science:
- Nephrology
- Virology
- Cell Biology
Background:
- HIV infection frequently leads to glomerular lesions, specifically focal segmental glomerulosclerosis.
- Mesangial expansion, characterized by increased mesangial cell (MC) proliferation and matrix accumulation, precedes focal segmental glomerulosclerosis development.
Purpose of the Study:
- To investigate the impact of HIV-1 gp160 protein and macrophage interactions on MC proliferation and matrix synthesis.
- To elucidate the role of transforming growth factor-beta (TGF-beta) in mediating these effects.
Main Methods:
- Cultured MCs were exposed to control media, macrophage supernatant (MSP), and gp160-treated MSP (gp160-MSP).
- Cell proliferation was assessed using cell counts and bromodeoxyuridine incorporation.
- Collagen type IV synthesis was quantified.
- The effect of anti-TGF-beta antibody was evaluated.
Main Results:
- MSP enhanced MC proliferation, while gp160-MSP inhibited it in a dose-dependent manner.
- gp160-MSP significantly increased collagen type IV synthesis by MCs, also in a dose-dependent manner.
- Anti-TGF-beta antibody attenuated the effects of gp160-MSP on both MC proliferation and collagen synthesis.
Conclusions:
- Macrophage-gp160 interaction products, potentially via TGF-beta, can modulate MC proliferation and collagen synthesis.
- These findings suggest a mechanism by which HIV-1 proteins contribute to mesangial expansion and kidney damage in HIV-infected patients.