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BioMed CentralPage 1 of 12(page number not for citation purposes)RetrovirologyOpen AccessResearchApoptosis resistance in HIV-1 persistently-infected cells is independent of active viral replication and involves modulation of the apoptotic mitochondrial pathwayPablo N Fernández Larrosa*1, Diego O Croci2, Diego A Riva3, Mariel Bibini1, Renata Luzzi1, Mónica Saracco1, Susana E Mersich3, Gabriel A Rabinovich2 and Liliana Martínez Peralta1Address: 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 and 3Laboratory of Virology, Department of Biochemistry, School of Exact and Natural Sciences, University of Buenos Aires, Buenos Aires, ArgentinaEmail: Pablo N Fernández Larrosa* - plarrosa@fmed.uba.ar; Diego O Croci - dcrocirusso@yahoo.com.ar; Diego A Riva - diegor@qb.fcen.uba.ar; Mariel Bibini - mbibini@yahoo.com; Renata Luzzi - rluzzi@fmed.uba.ar; Mónica Saracco - msaracco@fmed.uba.ar; Susana E Mersich - susanm@qb.fcen.uba.ar; Gabriel A Rabinovich - gabyrabi@ciudad.com.ar; Liliana Martínez Peralta - lilimp@fmed.uba.ar* Corresponding author AbstractBackground: 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 phaseof HIV infection, persistently-infected macrophages and quiescent T-cells seem to be resistant tocell death, representing a potential reservoir for virus production.Results: Lymphoid (H9/HTLVIIIB and J1.1) and pro-monocytic (U1) HIV-1 persistently-infected celllines were treated with hydrogen peroxide (H2O2) and staurosporine (STS) for 24 h, andsusceptibility to apoptosis was evaluated and compared with uninfected counterparts (H9, Jurkatand U937 respectively). When exposed to different pro-apoptotic stimuli, all persistently-infectedcell lines showed a dramatic reduction in the frequency of apoptotic cells in comparison withuninfected cells. This effect was independent of the magnitude of viral replication, since theinduction of viral production in lymphoid or pro-monocytic cells by exposure to TNF-α or PMAdid not significantly change their susceptibility to H2O2- or STS-induced cell death. A mechanisticanalysis revealed significant diferences in mitochondrial membrane potential (MMP) and caspase-3activation between uninfected and persistently-infected cells. In addition, Western blot assaysshowed 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 inpersistently-infected lymphoid and monocytic cells is independent of active viral production andinvolves modulation of the mitochondrial pathway. Understanding this effect is critical to specificallytarget the persistence of viral reservoirs, and provide insights for future therapeutic strategies inorder to promote complete viral eradication.Published: 8 February 2008Retrovirology 2008, 5:19doi:10.1186/1742-4690-5-19Received: 11 October 2007Accepted: 8 February 2008This article is available from: http://www.retrovirology.com/content/5/1/19© 2008 Fernández Larrosa et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.