Research

Apoptosis resistance in HIV-1 persistently-infected cells is independent of active viral replication and involves modulation of the apoptotic mitochondrial pathway

Pablo N Fernández Larrosa¹ , Diego O Croci² , Diego A Riva³ , Mariel Bibini¹ , Renata Luzzi¹ , Mónica Saracco¹ , Susana E Mersich³ , Gabriel A Rabinovich² and Liliana Martínez Peralta¹

¹National Reference Center for AIDS, Department of Microbiology, School of Medicine, University of Buenos Aires, Buenos Aires, Argentina

²Laboratory of Immunopathology, Institute of Biology and Experimental Medicine (IBYME), CONICET, Buenos Aires, Argentina

³Laboratory of Virology, Department of Biochemistry, School of Exact and Natural Sciences, University of Buenos Aires, Buenos Aires, Argentina

author email corresponding author email

Retrovirology 2008, 5:19doi:10.1186/1742-4690-5-19

Published:	8 February 2008

Abstract

Background

HIV triggers the decline of CD4⁺ T cells and leads to progressive dysfunction of cell-mediated immunity. Although an increased susceptibility to cell death occurs during the acute phase of HIV infection, persistently-infected macrophages and quiescent T-cells seem to be resistant to cell death, representing a potential reservoir for virus production.

Results

Lymphoid (H9/HTLVIII_B and J1.1) and pro-monocytic (U1) HIV-1 persistently-infected cell lines were treated with hydrogen peroxide (H₂O₂) and staurosporine (STS) for 24 h, and susceptibility to apoptosis was evaluated and compared with uninfected counterparts (H9, Jurkat and U937 respectively). When exposed to different pro-apoptotic stimuli, all persistently-infected cell lines showed a dramatic reduction in the frequency of apoptotic cells in comparison with uninfected cells. This effect was independent of the magnitude of viral replication, since the induction of viral production in lymphoid or pro-monocytic cells by exposure to TNF-α or PMA did not significantly change their susceptibility to H₂O₂- or STS-induced cell death. A mechanistic analysis revealed significant diferences in mitochondrial membrane potential (MMP) and caspase-3 activation between uninfected and persistently-infected cells. In addition, Western blot assays showed a dramatic reduction of the levels of pro-apototic Bax in mitochondria of persistently-infected cells treated with H₂O₂ or STS, but not in uninfected cells.

Conclusion

This study represents the first evidence showing that resistance to apoptosis in persistently-infected lymphoid and monocytic cells is independent of active viral production and involves modulation of the mitochondrial pathway. Understanding this effect is critical to specifically target the persistence of viral reservoirs, and provide insights for future therapeutic strategies in order to promote complete viral eradication.