Skip to main content
NCBI home page
Journal of Virology logoLink to Journal of Virology
. 1996 Aug;70(8):5447–5454. doi: 10.1128/jvi.70.8.5447-5454.1996

Alteration of intracellular potassium and sodium concentrations correlates with induction of cytopathic effects by human immunodeficiency virus.

T G Voss 1, C D Fermin 1, J A Levy 1, S Vigh 1, B Choi 1, R F Garry 1
PMCID: PMC190502  PMID: 8764056

Abstract

Increases in intracellular concentrations of potassium ([K+]i) and sodium ([Na+]i) occur concomitantly with cytopathic effects induced in a CD4+ T-lymphoblastoid cell line acutely infected by human immunodeficiency virus (HIV). This [K+]i increase was greater in cells infected by cytopathic HIV strains than in cells infected by less cytopathic strains. T cells persistently infected by HIV had an increased [K+]i but displayed an [Na+]i similar to that of mock-infected cells. HIV induced increases in [K+]i and [Na+]i after cytopathic infection of human peripheral blood mononuclear cells, but the magnitude of the Na+ changes did not correlate with the extent of the cytopathic effect. Enhanced movement of cations may osmotically drive water entry, resulting in balloon degeneration and lysis of HIV-infected cells. These observations offer potential approaches for antiviral therapies.

Full Text

The Full Text of this article is available as a PDF (2.1 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aldrovandi G. M., Zack J. A. Replication and pathogenicity of human immunodeficiency virus type 1 accessory gene mutants in SCID-hu mice. J Virol. 1996 Mar;70(3):1505–1511. doi: 10.1128/jvi.70.3.1505-1511.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Alonso M. A., Carrasco L. Reversion by hypotonic medium of the shutoff of protein synthesis induced by encephalomyocarditis virus. J Virol. 1981 Feb;37(2):535–540. doi: 10.1128/jvi.37.2.535-540.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Asjö B., Morfeldt-Månson L., Albert J., Biberfeld G., Karlsson A., Lidman K., Fenyö E. M. Replicative capacity of human immunodeficiency virus from patients with varying severity of HIV infection. Lancet. 1986 Sep 20;2(8508):660–662. [PubMed] [Google Scholar]
  4. Bader A. V., Bader J. P. Transformation of cells by rous sarcoma virus: cytoplasmic vacuolization. J Cell Physiol. 1976 Jan;87(1):33–46. doi: 10.1002/jcp.1040870106. [DOI] [PubMed] [Google Scholar]
  5. Bader J. P., Okazaki T., Brown N. R. Sodium and rubidium uptake in cells transformed by Rous sarcoma virus. J Cell Physiol. 1981 Feb;106(2):235–243. doi: 10.1002/jcp.1041060209. [DOI] [PubMed] [Google Scholar]
  6. Bader J. P., Sege R., Brown N. R. Sodium concentrations affect metabolite uptake and cellular metabolism. J Cell Physiol. 1978 May;95(2):179–188. doi: 10.1002/jcp.1040950207. [DOI] [PubMed] [Google Scholar]
  7. Baghian A., Kousoulas K. G. Role of the Na+,K+ pump in herpes simplex type 1-induced cell fusion: melittin causes specific reversion of syncytial mutants with the syn1 mutation to Syn+ (wild-type) phenotype. Virology. 1993 Oct;196(2):548–556. doi: 10.1006/viro.1993.1510. [DOI] [PubMed] [Google Scholar]
  8. Bashford C. L., Alder G. M., Menestrina G., Micklem K. J., Murphy J. J., Pasternak C. A. Membrane damage by hemolytic viruses, toxins, complement, and other cytotoxic agents. A common mechanism blocked by divalent cations. J Biol Chem. 1986 Jul 15;261(20):9300–9308. [PubMed] [Google Scholar]
  9. Benos D. J., Hahn B. H., Bubien J. K., Ghosh S. K., Mashburn N. A., Chaikin M. A., Shaw G. M., Benveniste E. N. Envelope glycoprotein gp120 of human immunodeficiency virus type 1 alters ion transport in astrocytes: implications for AIDS dementia complex. Proc Natl Acad Sci U S A. 1994 Jan 18;91(2):494–498. doi: 10.1073/pnas.91.2.494. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Borsa J., Sargent M. D., Long D. G., Chapman J. D. Extraordinary effects of specific monovalent cations on activation of reovirus transcriptase by chymotrypsin in vitro. J Virol. 1973 Feb;11(2):207–217. doi: 10.1128/jvi.11.2.207-217.1973. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Castrillo J. L., López-Rivas A., Carrasco L. Effects of extracellular cations on translation in poliovirus-infected cells. J Gen Virol. 1987 Feb;68(Pt 2):325–333. doi: 10.1099/0022-1317-68-2-325. [DOI] [PubMed] [Google Scholar]
  12. Cheng-Mayer C., Seto D., Tateno M., Levy J. A. Biologic features of HIV-1 that correlate with virulence in the host. Science. 1988 Apr 1;240(4848):80–82. doi: 10.1126/science.2832945. [DOI] [PubMed] [Google Scholar]
  13. Cloyd M. W., Lynn W. S. Perturbation of host-cell membrane is a primary mechanism of HIV cytopathology. Virology. 1991 Apr;181(2):500–511. doi: 10.1016/0042-6822(91)90882-c. [DOI] [PubMed] [Google Scholar]
  14. Dimitrov D. S., Broder C. C., Berger E. A., Blumenthal R. Calcium ions are required for cell fusion mediated by the CD4-human immunodeficiency virus type 1 envelope glycoprotein interaction. J Virol. 1993 Mar;67(3):1647–1652. doi: 10.1128/jvi.67.3.1647-1652.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Evans L. A., McHugh T. M., Stites D. P., Levy J. A. Differential ability of human immunodeficiency virus isolates to productively infect human cells. J Immunol. 1987 May 15;138(10):3415–3418. [PubMed] [Google Scholar]
  16. Evans L. A., Moreau J., Odehouri K., Legg H., Barboza A., Cheng-Mayer C., Levy J. A. Characterization of a noncytopathic HIV-2 strain with unusual effects on CD4 expression. Science. 1988 Jun 10;240(4858):1522–1525. doi: 10.1126/science.2836951. [DOI] [PubMed] [Google Scholar]
  17. Fenyö E. M., Morfeldt-Månson L., Chiodi F., Lind B., von Gegerfelt A., Albert J., Olausson E., Asjö B. Distinct replicative and cytopathic characteristics of human immunodeficiency virus isolates. J Virol. 1988 Nov;62(11):4414–4419. doi: 10.1128/jvi.62.11.4414-4419.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Fermin C. D., Garry R. F. Membrane alterations linked to early interactions of HIV with the cell surface. Virology. 1992 Dec;191(2):941–946. doi: 10.1016/0042-6822(92)90269-u. [DOI] [PubMed] [Google Scholar]
  19. Fermin C. D., Gerber M. A., Torre-Bueno J. R. Colour thresholding and objective quantification in bioimaging. J Microsc. 1992 Jul;167(Pt 1):85–95. doi: 10.1111/j.1365-2818.1992.tb03221.x. [DOI] [PubMed] [Google Scholar]
  20. Garry R. F. Alteration of intracellular monovalent cation concentrations by a poliovirus mutant which encodes a defective 2A protease. Virus Res. 1989 Jun;13(2):129–141. doi: 10.1016/0168-1702(89)90011-7. [DOI] [PubMed] [Google Scholar]
  21. Garry R. F., Bishop J. M., Parker S., Westbrook K., Lewis G., Waite M. R. Na+ and K+ concentrations and the regulation of protein synthesis in Sindbis virus-infected chick cells. Virology. 1979 Jul 15;96(1):108–120. doi: 10.1016/0042-6822(79)90177-6. [DOI] [PubMed] [Google Scholar]
  22. Garry R. F., Bostick D. A. Intracellular K+ and the expression of transformation parameters by chick cells transformed with the Bryan strain of Rous sarcoma virus. Virology. 1986 Apr 30;150(2):439–450. doi: 10.1016/0042-6822(86)90308-9. [DOI] [PubMed] [Google Scholar]
  23. Garry R. F., Gottlieb A. A., Zuckerman K. P., Pace J. R., Frank T. W., Bostick D. A. Cell surface effects of human immunodeficiency virus. Biosci Rep. 1988 Feb;8(1):35–48. doi: 10.1007/BF01128970. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Garry R. F., Koch G. Tat contains a sequence related to snake neurotoxins. AIDS. 1992 Dec;6(12):1541–1542. doi: 10.1097/00002030-199212000-00019. [DOI] [PubMed] [Google Scholar]
  25. Garry R. F., Kort J. J., Koch-Nolte F., Koch G. Similarities of viral proteins to toxins that interact with monovalent cation channels. AIDS. 1991 Nov;5(11):1381–1384. doi: 10.1097/00002030-199111000-00017. [DOI] [PubMed] [Google Scholar]
  26. Garry R. F. Potential mechanisms for the cytopathic properties of HIV. AIDS. 1989 Nov;3(11):683–694. doi: 10.1097/00002030-198911000-00001. [DOI] [PubMed] [Google Scholar]
  27. Garry R. F., Waite M. R. Na+ and K+ concentrations and the regulation of the interferon system in chick cells. Virology. 1979 Jul 15;96(1):121–128. doi: 10.1016/0042-6822(79)90178-8. [DOI] [PubMed] [Google Scholar]
  28. Garry R. F., Westbrook K., Waite M. R. Differential effects of ouabain on host- and sindbis virus-specified protein synthesis. Virology. 1979 Nov;99(1):179–182. doi: 10.1016/0042-6822(79)90051-5. [DOI] [PubMed] [Google Scholar]
  29. Gawrisch K., Han K. H., Yang J. S., Bergelson L. D., Ferretti J. A. Interaction of peptide fragment 828-848 of the envelope glycoprotein of human immunodeficiency virus type I with lipid bilayers. Biochemistry. 1993 Mar 30;32(12):3112–3118. doi: 10.1021/bi00063a024. [DOI] [PubMed] [Google Scholar]
  30. Grinstein S., Woodside M., Goss G. G., Kapus A. Osmotic activation of the Na+/H+ antiporter during volume regulation. Biochem Soc Trans. 1994 May;22(2):512–516. doi: 10.1042/bst0220512. [DOI] [PubMed] [Google Scholar]
  31. Henderson L. A., Qureshi N. M., Rasheed S., Garry R. Human immunodeficiency virus-induced cytotoxicity for CD8 cells from some normal donors and virus-specific induction of a suppressor factor. Clin Immunol Immunopathol. 1988 Aug;48(2):174–186. doi: 10.1016/0090-1229(88)90081-5. [DOI] [PubMed] [Google Scholar]
  32. Ho D. D., Neumann A. U., Perelson A. S., Chen W., Leonard J. M., Markowitz M. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature. 1995 Jan 12;373(6510):123–126. doi: 10.1038/373123a0. [DOI] [PubMed] [Google Scholar]
  33. Häussinger D., Lang F. Cell volume in the regulation of hepatic function: a mechanism for metabolic control. Biochim Biophys Acta. 1991 Dec 12;1071(4):331–350. doi: 10.1016/0304-4157(91)90001-d. [DOI] [PubMed] [Google Scholar]
  34. Knutton S., Bächi T. The role of cell swelling and haemolysis in Sendai virus-induced cell fusion and in the diffusion of incorporated viral antigens. J Cell Sci. 1980 Apr;42:153–167. doi: 10.1242/jcs.42.1.153. [DOI] [PubMed] [Google Scholar]
  35. Kollmann T. R., Kim A., Pettoello-Mantovani M., Hachamovitch M., Rubinstein A., Goldstein M. M., Goldstein H. Divergent effects of chronic HIV-1 infection on human thymocyte maturation in SCID-hu mice. J Immunol. 1995 Jan 15;154(2):907–921. [PubMed] [Google Scholar]
  36. Laurent-Crawford A. G., Krust B., Muller S., Rivière Y., Rey-Cuillé M. A., Béchet J. M., Montagnier L., Hovanessian A. G. The cytopathic effect of HIV is associated with apoptosis. Virology. 1991 Dec;185(2):829–839. doi: 10.1016/0042-6822(91)90554-o. [DOI] [PubMed] [Google Scholar]
  37. Levy J. A., Hoffman A. D., Kramer S. M., Landis J. A., Shimabukuro J. M., Oshiro L. S. Isolation of lymphocytopathic retroviruses from San Francisco patients with AIDS. Science. 1984 Aug 24;225(4664):840–842. doi: 10.1126/science.6206563. [DOI] [PubMed] [Google Scholar]
  38. Levy J. A. Pathogenesis of human immunodeficiency virus infection. Microbiol Rev. 1993 Mar;57(1):183–289. doi: 10.1128/mr.57.1.183-289.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Lipton S. A. Calcium channel antagonists and human immunodeficiency virus coat protein-mediated neuronal injury. Ann Neurol. 1991 Jul;30(1):110–114. doi: 10.1002/ana.410300121. [DOI] [PubMed] [Google Scholar]
  40. Lipton S. A. HIV-related neurotoxicity. Brain Pathol. 1991 Apr;1(3):193–199. doi: 10.1111/j.1750-3639.1991.tb00659.x. [DOI] [PubMed] [Google Scholar]
  41. Miller M. A., Cloyd M. W., Liebmann J., Rinaldo C. R., Jr, Islam K. R., Wang S. Z., Mietzner T. A., Montelaro R. C. Alterations in cell membrane permeability by the lentivirus lytic peptide (LLP-1) of HIV-1 transmembrane protein. Virology. 1993 Sep;196(1):89–100. doi: 10.1006/viro.1993.1457. [DOI] [PubMed] [Google Scholar]
  42. Miller M. A., Garry R. F., Jaynes J. M., Montelaro R. C. A structural correlation between lentivirus transmembrane proteins and natural cytolytic peptides. AIDS Res Hum Retroviruses. 1991 Jun;7(6):511–519. doi: 10.1089/aid.1991.7.511. [DOI] [PubMed] [Google Scholar]
  43. Miller M. A., Mietzner T. A., Cloyd M. W., Robey W. G., Montelaro R. C. Identification of a calmodulin-binding and inhibitory peptide domain in the HIV-1 transmembrane glycoprotein. AIDS Res Hum Retroviruses. 1993 Nov;9(11):1057–1066. doi: 10.1089/aid.1993.9.1057. [DOI] [PubMed] [Google Scholar]
  44. Pinto L. H., Holsinger L. J., Lamb R. A. Influenza virus M2 protein has ion channel activity. Cell. 1992 May 1;69(3):517–528. doi: 10.1016/0092-8674(92)90452-i. [DOI] [PubMed] [Google Scholar]
  45. Pritzen C., Herrmann A. Are osmotic forces involved in influenza virus-cell fusion? Biosci Rep. 1988 Feb;8(1):55–64. doi: 10.1007/BF01128972. [DOI] [PubMed] [Google Scholar]
  46. Rasheed S., Gottlieb A. A., Garry R. F. Cell killing by ultraviolet-inactivated human immunodeficiency virus. Virology. 1986 Oct 30;154(2):395–400. doi: 10.1016/0042-6822(86)90465-4. [DOI] [PubMed] [Google Scholar]
  47. Somasundaran M., Robinson H. L. A major mechanism of human immunodeficiency virus-induced cell killing does not involve cell fusion. J Virol. 1987 Oct;61(10):3114–3119. doi: 10.1128/jvi.61.10.3114-3119.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Srinivas S. K., Srinivas R. V., Anantharamaiah G. M., Segrest J. P., Compans R. W. Membrane interactions of synthetic peptides corresponding to amphipathic helical segments of the human immunodeficiency virus type-1 envelope glycoprotein. J Biol Chem. 1992 Apr 5;267(10):7121–7127. [PubMed] [Google Scholar]
  49. Terai C., Kornbluth R. S., Pauza C. D., Richman D. D., Carson D. A. Apoptosis as a mechanism of cell death in cultured T lymphoblasts acutely infected with HIV-1. J Clin Invest. 1991 May;87(5):1710–1715. doi: 10.1172/JCI115188. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Tersmette M., Gruters R. A., de Wolf F., de Goede R. E., Lange J. M., Schellekens P. T., Goudsmit J., Huisman H. G., Miedema F. Evidence for a role of virulent human immunodeficiency virus (HIV) variants in the pathogenesis of acquired immunodeficiency syndrome: studies on sequential HIV isolates. J Virol. 1989 May;63(5):2118–2125. doi: 10.1128/jvi.63.5.2118-2125.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Tsien R. Y. Intracellular measurements of ion activities. Annu Rev Biophys Bioeng. 1983;12:91–116. doi: 10.1146/annurev.bb.12.060183.000515. [DOI] [PubMed] [Google Scholar]
  52. Tsien R. Y. Intracellular signal transduction in four dimensions: from molecular design to physiology. Am J Physiol. 1992 Oct;263(4 Pt 1):C723–C728. doi: 10.1152/ajpcell.1992.263.4.C723. [DOI] [PubMed] [Google Scholar]
  53. Ulug E. T., Garry R. F., Bose H. R., Jr The role of monovalent cation transport in Sindbis virus maturation and release. Virology. 1989 Sep;172(1):42–50. doi: 10.1016/0042-6822(89)90105-0. [DOI] [PubMed] [Google Scholar]
  54. Ulug E. T., Garry R. F., Waite M. R., Bose H. R., Jr Alterations in monovalent cation transport in Sindbis virus-infected chick cells. Virology. 1984 Jan 15;132(1):118–130. doi: 10.1016/0042-6822(84)90096-5. [DOI] [PubMed] [Google Scholar]
  55. Vile R. G., Weiss R. A. Cell biology. Virus receptors as permeases. Nature. 1991 Aug 22;352(6337):666–667. doi: 10.1038/352666a0. [DOI] [PubMed] [Google Scholar]
  56. Voss T. G., Gatti P. J., Fermin C. D., Garry R. F. Reduction of human immunodeficiency virus production and cytopathic effects by inhibitors of the Na+/K+/2Cl- cotransporter. Virology. 1996 May 1;219(1):291–294. doi: 10.1006/viro.1996.0249. [DOI] [PubMed] [Google Scholar]
  57. Waite M. R., Pfefferkorn E. R. Inhibition of Sindbis virus production by media of low ionic strength: intracellular events and requirements for reversal. J Virol. 1970 Jan;5(1):60–71. doi: 10.1128/jvi.5.1.60-71.1970. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Wei X., Ghosh S. K., Taylor M. E., Johnson V. A., Emini E. A., Deutsch P., Lifson J. D., Bonhoeffer S., Nowak M. A., Hahn B. H. Viral dynamics in human immunodeficiency virus type 1 infection. Nature. 1995 Jan 12;373(6510):117–122. doi: 10.1038/373117a0. [DOI] [PubMed] [Google Scholar]
  59. Yada T., Vigh S., Arimura A. Pituitary adenylate cyclase activating polypeptide (PACAP) increases cytosolic-free calcium concentration in folliculo-stellate cells and somatotropes of rat pituitary. Peptides. 1993 Mar-Apr;14(2):235–239. doi: 10.1016/0196-9781(93)90035-f. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Virology are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES