CONCLUDING REMARKS

The following molecular sequence of events orchestrates the death of Env-induced syncytia in vitro: CDK1∕mTOR∕FRAP∕p53∕Bax∕MMP∕AIF and cytochrome c release/caspase activation/nuclear apo­ptosis (for reviews, see Castedo et al.^5,13).

The HIV-1-mediated pathways leading to cell death are complex and multiple yet sometimes overlap. Cell death can result from specific effects of the virus as well as from effects of viral isolated proteins and indirect effects mediated by the host.²⁴ For instance, at least in vitro, the induction of apoptosis by the HIV-1 proteins Tat, Pr, and Vpr, by syncytia formation and in bystander cells, favors the induction of MMP, which, in turn, coordinates the degradation phase of apoptosis (i.e., nuclear chromatin condensation, fragmentation, and so on). More precisely, Vpr, Pr, and Tat can interact physically with mitochondrial proteins such as ANT, Bcl-2, and the superoxide dis­mutase (SOD), respectively, and can act directly to induce MMP without the need of a signaling pathway upstream of the mitochondria. Then the CDK1∕mTOR∕FRAP∕p53∕Bax activation cascade that is triggered in response to the interaction of Env with CD4 and CXCR4 or CCR5 may be specific to the Env-mediated syncytial death, whereas the activation of mitochondria and caspases that are subsequent to Bax activation is common to the general mitochondrial apoptosis pathway.

In the future, it is important to determine whether this cascade of events occurs within syncytia formed from the fusion of various cell types and how host factors (e.g., cytokine production profile, metabolic activity, and redox state of the fused cells) affect this cascade of events to modulate the fate of syncytia in vivo.

ACKNOWLEDGMENTS

Our work was supported by grants funded by ARC (to CB), CNRS (to CB), and the French Ministry of Research (to CB).

REFERENCES

1. Pantaleo, G. and Fauci, A., Apoptosis in HIV infection, Nat. Med., 1, 118-120, 1995.

2. Badley, A.D., Pilon, A.A., Landay, A., and Lynch, D.H., Mechanisms of HIV-associated lymphocyte apoptosis, Blood, 96, 2951-2964, 2000.

3. Gougeon, M., Apoptosis as an HIV strategy to escape immune attack, Nat. Rev. Immunol., 3, 392-404, 2003.

4. Alimonti, J.B., Ball, T.B., and Fowke, K.R., Mechanisms of CD4+ T lymphocyte cell death in human immunodeficiency virus infection and AIDS, J. Gen. Virol., 84, 1649-1661, 2003.

5. Castedo, M., Perfettini, J., Andreau, K., Roumier, T., Piacentini, M., and Kroemer, G., Mitochondrial apoptosis induced by the HIV-1 envelope, Ann. N.Y. Acad. Sci., 1010, 19-28, 2003.

6. Ferri, K.F., Jacotot, E., Blanco, J., Este, J.A., Zamzami, N., Susin, S.A., Xie, Z., Brothers, G., Reed, J.C., Penninger, J.M., and Kroemer, G., Apoptosis control in syncytia induced by the HIV type 1- envelope glycoprotein complex. Role of mitochondria and caspases, J. Exp. Med., 192, 1081-1092,

2000.

7. Castedo, M., Ferri, K.F., Blanco, J., Roumier, T., Larochette, N., Barretina, J., Amendola, A., Nardacci, R., Metivier, D., Este, J.A., Piacentini, M., and Kroemer, G., Human immunodeficiency virus 1 envelope glycoprotein complex-induced apoptosis involves mammalian target of rapamycin∕FKBP12- rapamycin-associated protein-mediated p53 phosphorylation, J. Exp. Med., 194, 1097-1110, 2001.

8. Castedo, M., Roumier, T., Blanco, J., Ferri, K., Barretina, J., Tintignac, L., Andreau, K., Perfettini, J., Amendola, A., Nardacci, R., Leduc, P., Ingber, D., Druillennec, S., Roques, B., Leibovitch, S., Vilella-Bach, M., Chen, J., Este, J., Modjtahedi, N., Piacentini, M., and Kroemer, G., Sequential involvement of Cdk1, mTOR and p53 in apoptosis induced by the human immunodeficiency virus-1 envelope, EMBO J., 21, 4070-4080, 2002.

9. Perfettini, J., Roumier, T., Castedo M., Larochette, N., Boya, P., Reynal, B., Lazar, V., Ciccosanti, R., Nardacci, R., Penninger, J., Piacentini, M., and Kroemer, G., NF-B and p53 are the dominant apoptosis­inducing transcription factors elicited by the HIV-1 envelope, J. Exp. Med., (201) 279-289, 2004.

10. Anderson, J.M., Multinucleated giant cells, Curr. Opin. Hematol., 7, 40-47, 2000.

11. Blanco, J., Barretina, J., Ferri, K., Jacotot, E., Gutierrez, A., Cabrera, M., Kroemer, G., Clotet, B., and Este, J.A., Cell-surface-expressed HIV-1 envelope induces the death of CD4 T cells during GP41- mediated hemifusion-like events, Virology, 305, 356-365, 2003.

12. Munoz-Barroso, I., Durell, S., Sakaguchi, K., Appella, E., and Blumenthal, R., Dilation of the human immunodeficiency virus-1 envelope glycoprotein fusion pore revealed by the inhibitory action of a synthetic peptide from gp41, J. Cell Biol., 140, 315-323, 1998.

13. Castedo, M., Perfettini, J.-L., Roumier, T., and Kroemer, G., Cyclin-dependent kinase-1: linking apoptosis to cell cycle and mitotic catastrophe, Cell Death Diff., (9) 1287-1293, 2003.

14. Nakano, K. and Vousden, K.H., PUMA, a novel proapoptotic gene, is induced by p53, Mol. Cell, 7, 683-694, 2001.

15. Scaffidi, C., Fulda, S., Srinivasan, A., Friesen, C., Li, F., Tomaselli, K., Debatin, K., Krammer, P., and Peter, P., Two CD95 (APO-1∕Fas) signaling pathways, EMBO J., 17, 1675-1687, 1998.

16. Petit, F., Arnoult, D., Viollet, L., and Estaquier, J., Intrinsic and extrinsic pathways signaling during HIV-1 mediated cell death, Biochimie, 85, 795, 2003.

17. Kroemer, G. and Reed, J., Mitochondrial control of cell death, Nat. Med., 6, 513-519, 2000.

18. Liu, X., Kim, C.N., Yang, J., Jemmerson, R., and Wang, X., Induction of apoptotic program in cell- free extracts: requirement for dATP and cytochrome c, Cell, 86, 147-157, 1996.

19. Li, L.Y., Luo, X., and Wang, X., Endonuclease G is an apoptotic DNase when released from mito­chondria, Nature, 412, 95-99, 2001.

20. Susin, S.A., Zamzami, N., Castedo, M., Hirsch, T., Marchetti, P., Macho, A., Daugas, E., Geuskens, M., and Kroemer, G., Bcl-2 inhibits the mitochondrial release of an apoptogenic protease, J. Exp. Med., 184, 1331-1341, 1996.

21. Martinou, J.C., Desagher, S., and Antonsson, B., Cytochrome c release from mitochondria: all or nothing, Nat. Cell Biol., 2, E41-E43, 2000.

22. Shimizu, S., Matsuoka, Y., Shinohara, Y., Yoneda, Y., and Tsujimoto, Y., Essential role of voltage­dependent anion channel in various forms of apoptosis in mammalian cells, J. Cell Biol., 152, 237-250,

2001.

23. Halestrap, A. and Brenner, C., The adenine nucleotide translocase: a central component of the mitochondrial permeability transition pore and key player in cell death, Curr. Med. Chem., 10, 1507-1525, 2003.

24. Badley, A., Roumier, T., Lum, J.L., and Kroemer, G., Mitochondrion-mediated apoptosis in HIV-1 infection, Trends Pharmacol. Sci., 24, 298-305, 2003.