CONCLUSIONS

Although it is understood that HIV PR is cytotoxic in systems in which it is expressed independently, it is less certain whether HIV PR can and does induce cell death in the context of viral infection.

Moreover, the molecular mechanisms governing the initiation of PR-induced cell death remain controversial; however, PR-mediated cleavage of procaspase-8, Bcl-2, eIF4G, and cytoskeletal proteins is likely involved. We propose that low-level expression of PR favors the selective cleavage of these regulatory proteins favoring an apoptotic phenotype, whereas higher levels of expression may favor more extensive proteolysis, favoring an autophagocytic or necrotic phenotype. Whether PR-mediated cell death plays a clinically significant role in patients also remains controversial; however, indirect evidence suggests that in patients with immunologic discordance, mutations within PR may be contributory. Additional research directed at each of these controversies will undoubtedly resolve such controversies.

REFERENCES

1. Iwakura, Y., Shioda, T., Tosu, M., Yoshida, E., Hayashi, M., Nagata, T., and Shibuta, H. The induction of cataracts by HIV-1 in transgenic mice, AIDS, 6, 1069-1075, 1992.

2. Bettelheim, F.A., Zeng, F.F., Bia, Y., Tumminia, S.J., and Russell, P., Lens hydration in transgenic mice containing HIV-1 protease linked to the lens -A-crystallin promoter, Arch. Biochem. Biophys., 20(324), 2, 1995.

3. Bettelheim, F.A., Churchill, A.C., Siew, E.L., Tumminia, S.J., and Russell, P., Light scattering and morphology of cataract formation in transgenic mice containing the HIV-1 protease linked to the lens -A-crystallin promoter, Exp. Eye Res., 64(5), 667-674, 1997.

4. Tumminia, S.J., Clark, J.I., Richiert, D.M., Mitton, K.P., Duglas-Tabor, Y., Kowalak, J.A., Garland, D.L., and Russell, P., Three distinct stages of lens opacification in transgenic mice expressing the HIV-1 protease, Exp.

Eye Res., 72(2), 115-121, 2001.

5. Tumminia, S.J., Jonak, G.J., Focht, R.J., Cheng, Y.S., and Russell, P., Cataractogenesis in transgenic mice containing the HIV-1 protease linked to the lens -A-crystallin promoter, J. Biol. Chem., 271(1), 425-431, 1996.

6. Mitton, K.P., Kamiya, T., Tumminia, S.J., and Russell, P., Cysteine protease activated by expression of HIV-1 protease in transgenic mice. MIP26 (aquaporin-0) cleavage and cataract formation in vivo and ex vivo, J. Biol. Chem., 271(50), 31803-31806, 1996.

7. Blanco, R., Carrasco, L., and Ventoso, I., Cell killing by HIV-1 protease, J. Biol. Chem., 278(2), 1086-1093, 2003.

8. Strack, P.R., Frey, M.W., Rizzo, C.J., Cordova, B., George, H.J., Meade, R., Ho, S.P., Corman, J., Tritch, R., and Korant, B.D., Apoptosis mediated by HIV protease is preceded by cleavage of Bcl-2, Proc. Natl. Acad. Sci. U.S.A., 93(18), 9571-9576, 1996.

9. Korant, B.D., Strack, P.R., Frey, M.W., and Rizzo, C.J., A cellular anti-apoptosis protein is cleaved by the HIV-1 protease, Adv. Exp. Med. Biol., 436, 27-29, 1998.

10. Reed, J.D., Double identity for proteins of the Bcl-2 family, Nature, 387(6635), 773-776, 1997.

11. Kirkin, V., Joos, S., and Zornig, M., The role of Bcl-2 family members in tumorigenesis, Biochim. Biophys. Acta, 1644(2-3), 229-249, 2004.

12. Cory, S., Huang, D.C., and Adams, J.M., The Bcl-2 family: roles in cell survival and oncongenesis, Oncogene, 22(53), 8590-8607, 2003.

13. Rapp, U.R., Rennefahrt, U., and Troppmair, J., Bcl-2 proteins: master switches at the intersection of death signaling and the survival control by Raf kinases, Biochim. Biophys. Acta, 1644(2-3), 149-158, 2004.

14. Cheng, E.H., Kirsch, D.G., Clem, R.J., Ravi, R., Kastan, M.B., Bedi, A., Ueno, K., and Wardwick,

J. M., Conversion of Bcl-2 to a Bax-like death effector by caspases, Science, 278(5345), 1966-1968, 1997.

15. Cohen, G.M., Caspases: the executioners of apoptosis, Biochem. J., 326(Pt. 1), 1-16, 1997.

16. Chang, H.Y.

and Yang, X., Proteases for cell suicide: functions and regulation of caspases, Microbiol. Mol. Biol. Rev., 64(4), 821-846, 2000.

17. Bitzer, M., Prinz, F., Bauer, M., Spiegel, M., Neubert, W.J., Gregor, M., Schulze-Osthoff, K., and Lauer, U., Sendai virus infection induces apoptosis through activation of caspase-8 (FLICE) and caspase-3 (CPP32), J. Virol., 73(1), 702-708, 1999.

18. Thome, M., Schneider, P., Hofmann, K., Fickenscher, H., Meinl, E., Neipel, F., Mattmann, C., Burns,

K., Bodmer, J.L., Schroter, M., Scaffidi, C., Krammer, P.H., Peter, M.E., and Tschopp, J., Viral FLICE- inhibitory proteins (FLIPs) prevent apoptosis induced by death receptors, Nature, 386(6624), 517-521, 1997.

19. Nie, Z., Phenix, B.N., Lum, J.J., Alam, A., Lynch, D.H., Beckett, B., Krammer, P.H., Sekaly, R.P., and Badley, A.D., HIV-1 protease processes procaspase-8 to cause mitochondrial release of cytochrome c, caspase cleavage and nuclear fragmentation, Cell Death Differ., 9(11), 1172-1184, 2002.

20. Shoeman, R.L., Honer, B., Stoller, T.J., Kesselmeier, C., Miedel, M.C., Traub, P., and Graves, M.C., Human immunodeficiency virus type 1 protease cleaves the intermediate filament proteins vimentin, desmin, and glial fibrillary acidic protein, Proc. Natl. Acad. Sci. U.S.A., 87(16), 6336-6340, 1990.

21. Tomasselli, A.G., Hui, J.O., Adams, L., Chosay, J. Lowery, D., Greenberg, B., Yem, A., Deibel, M.R., Zurcher-Neely, H., and Heinrikson, R.L., Actin, troponin C, Alzheimer amyloid precursor protein and pro-interleukin 1 as substrates of the protease from human immunodeficiency virus, J. Biol. Chem., 266(22), 14548-14553, 1991.

22. Adams, L.D., Tommasselli, A.G., Robbins, P., Moss, B., and Heinrikson, R.L., HIV-1 protease cleaves actin during acute infection of human T-lymphocytes, AIDS Res. Hum. Retroviruses, 8(2), 291-295, 1992.

23. Shoeman, R.L., Sachse, C., Honer, B., Mothes, E., Kaufmann, M., and Traub, P., Cleavage of human and mouse cytoskeletal and sarcomeric proteins by human immunodeficiency virus type 1 protease.

Actin, desmin, myosin, and tropomyosin, Am. J. Pathol., 142(1), 221-230, 1993.

24. Shoeman, R.L., Huttermann, C., Hartig, R., and Traub, P., Amino-terminal polypeptides of vimentin are responsible for the changes in nuclear architecture associated with human immunodeficiency virus type 1 protease activity in tissue culture cells, Mol. Biol. Cell, 12(1), 143-154, 2001.

25. Ventoso, I., Blanco, R., Perales, C., and Carrasco, L., HIV-1 protease cleaves eukaryotic initiation factor 4G and inhibits cap-dependent translation, Proc. Natl. Acad. Sci. U.S.A., 98(23), 12966-12971, 2001.

26. Ohlmann, T., Prevot, D., Decimo, D., Roux, F., Garin, J., Morley, S.J., and Darlix, J.L., In vitro cleavage of eIF4GI but not eIF4GII by HIV-1 protease and its effects on translation in the rabbit reticulocyte lysate system, J. Mol. Biol., 318(1), 9-20, 2002.

27. Shoeman, R.L., Hartig, R., Hauses, C., and Traub, P., Organization of focal adhesion plaques is disrupted by action of the HIV-1 protease, Cell Biol. Int., 26(6), 529-539, 2002.

28. Coleman, M.L., Sahai, E.A., Yeo, M., Bosch, M., Dewar, A., and Olson, M.F., Membrane blebbing during apoptosis results from caspase-mediated activation of ROCK I, Nat. Cell Biol., 3(4), 339-345, 2001.

29. Coleman, M.L. and Olson, M.F., Rho GTPase signalling pathways in the morphological changes associates with apoptosis, Cell Death Differ., 9(5), 493-504, 2002.

30. Grzanka, A., Grzanka, D., and Orlikowska, M., Cytoskeletal reorganization during process of apoptosis induced by cytostatic drugs in K-562 and HL-60 leukemia cell lines, Biochem. Pharmacol., 66(8), 1611-1617, 2003.

31. Perales, C., Carrasco, L., and Ventoso, I., Cleavage of eIF4G by HIV-1 protease: effects on translation, FEBS Lett., 533(1-3), 89-94, 2003.

32. Alvarez, E., Menendez-Arias, L., and Carrasco, L., The eukaryotic translation initiation factor 4GI is cleaved by different retroviral proteases, J. Virol., 77(23), 12392-400, 2003.

33. Cauwels, A., Janssen, B., Waeytens, A., Cuvelier, C., and Brouckaert, P., Caspase inhibition causes hyperacute tumor necrosis factor-induced shock via oxidative stress and phospholipase A2, Nat.

Immunol., 4(4), 387-393, 2003.

34. Vanden Berghe, T., van Loo, G., Saelens, X., Van Gurp, M., Brouckaert, G., Kalai, M., Declercq, W., and Vandenabeele, P., Differential signaling to apoptotic and necrotic cell death by Fas-associated death domain protein FADD, J. Biol. Chem., 279(9), 7925-7933, 2004.

35. Li, W., Yuan, X., Nordgren, G., Dalen, H., Dubowchik, G.M., Firestone, R.A., and Brunk, U.T., Induction of cell death by the lysosomotropic detergent MSDH, FEBS Lett., 470(1), 35-39, 2000.

36. Piketty, C., Castiel, P., Belec, L., Batisse, D., Si Mohamed, A., Gilquin, J., Gonzalez-Canali, G., Jayle, D., Karmochkine, M., Weiss, L., Aboulker, J.P., and Kazatchkine, M.D., Discrepant responses to triple combination antiretroviral therapy in advanced HIV disease, AIDS, 12(7), 745-750, 1998.

37. Mezzaroma, I., Carlesimo, M., Pinter, E., Muratori, D.S., Di Sora, F., Chiarotti, F., Cunsolo, M.G., Sacco, G., and Aiuti, F., Clinical and immunologic response without decrease in virus load in patients with AIDS after 24 months of highly active antiretroviral therapy, Clin. Infect. Dis., 29(6), 1423-1430, 1999.

38. Ledergerber, B., Egger, M., Erard, V., Weber, R., Hirschel, B., Furrer, H., Battegay, M., Vernazza, P., Bernasconi, E., Opravil, M., Kaufmann, D., Sudre, P., Francioli, P., and Telenti, A., Clinical progression and virological failure on highly active antiretroviral therapy in HIV-1 patients: a prospective cohort study. Swiss HIV Cohort Study, Lancet, 353(9156), 863-868, 1999.

39. Grabar, S., Le Moing, V., Goujard, C., Leport, C., Kazatchkine, M.D., Costagliola, D., and Weiss, L., Clinical outcome of patients with HIV-1 infection according to immunologic and virologic response after 6 months of highly active antiretroviral therapy, Ann. Intern. Med., 133(6), 401-410, 2000.

40. Autran, B., Carcelain, G., Li, T.S., Blanc, C., Mathez, D., Tubiana, R., Katlama, C., Debre, P., and Leibowitch, J., Positive effects of combined antiretroviral therapy on CD4⁺ T cell homeostasis and function in advanced HIV disease, Science, 277(5322), 112-116, 1997.

41. Kaufmann, D., Pantaleo, G., Sudre, P., and Telenti, A., CD4-cell count in HIV-1-infected individuals remaining viraemic with highly active antiretroviral therapy (HAART). Swiss HIV Cohort Study, Lancet, 351(9104), 723-724, 1998.

42. Deeks, S.G., Hecht, F.M., Swanson, M., Elbeik, T., Loftus, R., Cohen, P.T., and Grant, R.M., HIV RNA and CD4 cell count response to protease inhibitor therapy in an urban AIDS clinic: response to both initial and salvage therapy, AIDS, 13(6), F35-F43, 1999.

43. Croteau, G., Doyon, L., Thibeault, D., McKercher, G., Pilote, L., and Lamarre, D., Impaired fitness of human immunodeficiency virus type 1 variants with high-level resistance to protease inhibitors, J. Virol., 71(2), 1089-1096, 1997.

44. Mammano, F., Petit, C., and Clavel, F., Resistance-associated loss of viral fitness in human immunodeficiency virus type 1: phenotypic analysis of protease and Gag coevolution in protease inhibitor- treated patients: loss of viral fitness associated with multiple Gag and Gag-Pol processing defects in human immunodeficiency virus type 1 variants selected for resistance to protease inhibitors in vivo, J. Virol., 72(9), 7632-7637, 1998.

45. Zennou, V., Mammano, F., Paulous, S., Mathez, D., and Clavel, F., Loss of viral fitness associated with multiple Gag and Gag-Pol processing defects in human immunodeficiency virus type 1 variants selected for resistance to protease inhibitors in vivo, J. Virol., 72(4), 3300-3306, 1998.

46. Martinez-Picado, J., Savara, A.V., Sutton, L., and D'Aquila, R.T., Replicative fitness of protease inhibitor-resistant mutants of human immunodeficiency virus type 1, J. Virol., 73(5), 3744-3752, 1999.

47. Mammano, F., Trouplin, V., Zennous, V., and Clavel, F., Retracing the evolutionary pathways of human immunodeficiency virus type 1 resistance to protease inhibitors: virus fitness in the absence and in the presence of drug, J. Virol., 74(18), 8524-8531, 2000.

48. Maree, A.F., Keulen, W., Boucher, C.A., and De Boer, R.J., Estimating relative fitness in viral competition experiments, J. Virol., 74(23), 11067-11072, 2000.

49. Quinones-Mateu, M.E., Ball, S.C., Marozsan, A.J., Torre, V.S., Albright, J.L., Vanham, G., van Der Groen, G., Colebunders, R.L., and Arts, E.J., A dual infection/competition assay shows a correlation between ex vivo human immunodeficiency virus type 1 fitness and disease progression, J. Virol., 74(19), 9222-9233, 2000.

50. Stoddart, C.A., Liegler, T.J., Mammano, F., Linquist-Stepps, V.D., Hayden, M.S., Deeks, S.G., Grant, R.M., Clavel, F., and McCune, J.M., Impaired replication of protease inhibitor-resistant HIV-1 in human thymus, Nat. Med., 7(6), 712-718, 2001.

51. Peng, C., Ho, B.K., Chang, T.W., and Chang, N.T., Role of human immunodeficiency virus type 1- specific protease in core protein maturation and viral infectivity, J. Virol., 63(6), 2550-2556, 1989.

52. Pomerantz, R.J. and Horn, D.L., Twenty years of therapy for HIV-1 infection, Nat. Med., 9(7), 867-873, 2003.

53. Palella, F.J., Jr., Delaney, K.M., Moorman, A.C., Loveless, M.O., Fuhrer, J., Satten, G.A., Aschman, D.J., and Holmberg, S.D., Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators, N. Engl. J. Med., 338(13), 853-860, 1998.

54. Boden, D. and Markowitz, M., Resistance to human immunodeficiency virus type 1 protease inhibitors, Antimicrob. Agents Chemother., 42(11), 2775-2783, 1998.

55. Cornelissen, M., Kampinga, G., Zorgdrager, F., and Goudsmit, J., Human immunodeficiency virus type 1 subtypes defined by Env show high frequency of recombinant gag genes. The UNAIDS Network for HIV Isolation and Characterization, J. Virol., 70(11), 8209-8212, 1996.

56. Clavel, F. and Hance, A.J., HIV drug resistance, N. Engl. J. Med., 350(10), 1023-1035, 2004.

57. Hertogs, K., Bloor, S., Kemp, S.D., Van den Eynde, C., Alcorn, T.M., Pauwels, R., Van Houtte, M., Staszewski, S., Miller, V., and Larder, B.A., Phenotypic and genotypic analysis of clinical HIV-1 isolates reveals extensive protease inhibitor cross-resistance: a survey of over 6000 samples, AIDS, 14(9), 1203-1210, 2000.

58. Kuroda, M.J., el-Farrash, M.A., Choudhury, S., and Harada, S., Impaired infectivity of HIV-1 after a single point mutation in the POL gene to escape the effect of a protease inhibitor in vitro, Virology, 210(1), 212-216, 1995.

59. Martinez-Picado, J., Savara, A.V., Shi, L., Sutton, L., and D'Aquila, R.T., Fitness of human immunodeficiency virus type 1 protease inhibitor-selected single mutants, Virology, 275(2), 318-322, 2000.

60. Devereux, H.L., Emery, V.C., Johnson, M.A., and Loveday, C., Replicative fitness in vivo of HIV-1 variants with multiple drug resistance-associated mutations, J. Med. Virol., 65(2), 218-224, 2001.

61. Bally, F., Martinez, R., Peters, S., Sudre, P., and Telenti, A., Polymorphism of HIV type 1 Gag p7/p1 and p1/p6 cleavage sites: clinical significance and implications for resistance to protease inhibitors, AIDS Res. Hum. Retroviruses, 16(13), 1209-1213, 2000.

62. Nijhuis, M., Schuurman, R., de Jong, D., Erickson, J., Gustchina, E., Albert, J., Schipper, P., Gulnik, S., and Boucher, C.A., Increased fitness of drug resistant HIV-1 protease as a result of acquisition of compensatory mutations during suboptimal therapy, AIDS, 13(17), 2349-2359, 1999.

63. Kim, E.Y., Winters, M.A., Kagan, R.M., and Merigan, T.C., Functional correlates of insertion mutations in the protease gene of human immunodeficiency virus type 1 isolates from patients, J. Virol., 75(22), 11227-11233, 2001.

64. Maguire, M.F., Guinea, R., Griffin, P., Macmanus, S., Elston, R.C., Wolfram, J., Richards, N., Hanlon, M.H., Porter, D.J., Wrin, T., Parkin, N., Tisdale, M., Furfine, E., Petropoulos, C., Snowden, B.W., and Kleim, J.P., Changes in human immunodeficiency virus type 1 Gag at positions L449 and P453 are linked to I50V protease mutants in vivo and cause reduction of sensitivity to amprenavir and improved viral fitness in vitro, J. Virol., 76(15), 7398-7406, 2002.

65. de la Carriere, L.C., Paulous, S., Clavel, F., and Mammano, F., Effects of human immunodeficiency virus type 1 resistance to protease inhibitors on reverse transcriptase processing, activity, and drug sensitivity, J. Virol., 73(4), 3455-3459, 1999.

66. Bleiber, G., Munoz, M., Ciuffi, A., Meylan, P., and Telenti, A., Individual contributions of mutant protease and reverse transcriptase to viral infectivity, replication, and protein maturation of antiretroviral drug-resistant human immunodeficiency virus type 1, J. Virol., 75(7), 3291-3300, 2001.

67. Konvalinka, J., Litterst, M.A., Welker, R., Kottler, H., Rippmann, F., Heuser, A.M., and Krausslich, H.G., An active-site mutation in the human immunodeficiency virus type 1 proteinase (PR) causes reduced PR activity and loss of PR-mediated cytotoxicity without apparent effect on virus maturation and infectivity, J. Virol., 69(11), 7180-7186, 1995.

68. Rose, J.R., Babe, L.M., and Craik, C.S., Defining the level of human immunodeficiency virus type 1 (HIV-1) protease activity required for HIV-1 particle maturation and infectivity, J. Virol., 69(5), 2751-2758, 1995.

69. Barbour, J.D., Hecht, F.M., Wrin, T., Segal, M.R., Ramstead, C.A., Liegler, T.J., Busch, M.P., Petropoulos, C.J., Hellmann, N.S., Kahn, J.O., and Grant, R.M. Higher CD4+ T cell counts associated with low viral pol replication capacity among treatment-naive adults in early HIV-1 infection. J. Infect. Dis., 190, 251-256, 2004.

<< | >>

↑

Source: Badley A.D. (ed.). Cell Death During HIV Infection. Taylor & Francis,2006. — 511 p.. 2006

More medical literature on Medic.Studio

CONCLUSIONS

More on the topic CONCLUSIONS: