Skip to main content
NCBI home page
Journal of Virology logoLink to Journal of Virology
. 1994 Nov;68(11):7490–7496. doi: 10.1128/jvi.68.11.7490-7496.1994

Tissue-mediated selection of viral variants: correlation between glycoprotein mutation and growth in neuronal cells.

L Villarete 1, T Somasundaram 1, R Ahmed 1
PMCID: PMC237191  PMID: 7933132

Abstract

Viral variants with different biological properties predominate in the central nervous system (CNS) and lymphoid tissues of carrier mice infected at birth with the Armstrong strain of lymphocytic choriomeningitis virus. The CNS isolates have the same phenotype as the parental strain and cause acute infections in adult mice, while the spleen-derived isolates cause chronic infections associated with suppressed T-cell responses and susceptibility to opportunistic infections. Our previous studies have identified a single amino acid change in the viral glycoprotein, a phenylalanine-to-leucine (F-->L) mutation at residue 260, that correlates with the tissue-specific selection and the persistent and immunosuppressive phenotype of the spleen isolates (R. Ahmed, C.S. Hahn, T. Somasundaram, L. Villarete, M. Matloubian, and J. H. Strauss, J. Virol. 65:4242-4247, 1991). In this study, we screened viral isolates obtained from the spleen, liver, kidney, and brain of carrier mice for the presence of this mutation and determined the temporal selection of variants as they appear in these organs. We found that this F-->L amino acid change is common to > 90% of the spleen and liver isolates and is selected for rapidly by day 32 postinfection (p.i.). Although the kinetics observed in the kidney are relatively slower than in the spleen and liver, this F-->L mutation predominates in the kidney-derived isolates by 250 days p.i. In contrast, the majority of the CNS isolates retain the parental sequence up to 250 days p.i. In addition, most of the brain isolates replicated efficiently in a neuronal cell line, and this enhanced growth phenotype in neurons correlated with the parental F genotype. This linkage with neurotropism, along with our earlier finding that the F-->L mutation is necessary for enhanced infection of macrophages (M. Matloubian, S. R. Kolhekar, T. Somasundaram, and R. Ahmed, J. Virol. 67:7340-7349, 1993), provides a cellular basis for the molecular changes associated with tissue-specific selection. Taken together, these results suggest that tropism for macrophages is a critical determinant in selection of variants with the F-->L mutation in tissues such as spleen and liver, and tropism for neurons is important in retention of the F genotype in the CNS.

Full text

PDF
7490

Images in this article

7491Image
on p.7491

Selected References

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

  1. Abdel-Hamid M., Chen J. J., Constantine N., Massoud M., Raab-Traub N. EBV strain variation: geographical distribution and relation to disease state. Virology. 1992 Sep;190(1):168–175. doi: 10.1016/0042-6822(92)91202-6. [DOI] [PubMed] [Google Scholar]
  2. Ahmed R., Hahn C. S., Somasundaram T., Villarete L., Matloubian M., Strauss J. H. Molecular basis of organ-specific selection of viral variants during chronic infection. J Virol. 1991 Aug;65(8):4242–4247. doi: 10.1128/jvi.65.8.4242-4247.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Ahmed R., King C. C., Oldstone M. B. Virus-lymphocyte interaction: T cells of the helper subset are infected with lymphocytic choriomeningitis virus during persistent infection in vivo. J Virol. 1987 May;61(5):1571–1576. doi: 10.1128/jvi.61.5.1571-1576.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Ahmed R., Oldstone M. B. Organ-specific selection of viral variants during chronic infection. J Exp Med. 1988 May 1;167(5):1719–1724. doi: 10.1084/jem.167.5.1719. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Ahmed R., Salmi A., Butler L. D., Chiller J. M., Oldstone M. B. Selection of genetic variants of lymphocytic choriomeningitis virus in spleens of persistently infected mice. Role in suppression of cytotoxic T lymphocyte response and viral persistence. J Exp Med. 1984 Aug 1;160(2):521–540. doi: 10.1084/jem.160.2.521. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Allan J. E., Dixon J. E., Doherty P. C. Nature of the inflammatory process in the central nervous system of mice infected with lymphocytic choriomeningitis virus. Curr Top Microbiol Immunol. 1987;134:131–143. doi: 10.1007/978-3-642-71726-0_6. [DOI] [PubMed] [Google Scholar]
  7. Borrow P., Tishon A., Oldstone M. B. Infection of lymphocytes by a virus that aborts cytotoxic T lymphocyte activity and establishes persistent infection. J Exp Med. 1991 Jul 1;174(1):203–212. doi: 10.1084/jem.174.1.203. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Buchmeier M. J., Parekh B. S. Protein structure and expression among arenaviruses. Curr Top Microbiol Immunol. 1987;133:41–57. doi: 10.1007/978-3-642-71683-6_4. [DOI] [PubMed] [Google Scholar]
  9. Buchmeier M. J., Southern P. J., Parekh B. S., Wooddell M. K., Oldstone M. B. Site-specific antibodies define a cleavage site conserved among arenavirus GP-C glycoproteins. J Virol. 1987 Apr;61(4):982–985. doi: 10.1128/jvi.61.4.982-985.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Buchmeier M. J., Welsh R. M., Dutko F. J., Oldstone M. B. The virology and immunobiology of lymphocytic choriomeningitis virus infection. Adv Immunol. 1980;30:275–331. doi: 10.1016/s0065-2776(08)60197-2. [DOI] [PubMed] [Google Scholar]
  11. Burns J. W., Buchmeier M. J. Protein-protein interactions in lymphocytic choriomeningitis virus. Virology. 1991 Aug;183(2):620–629. doi: 10.1016/0042-6822(91)90991-j. [DOI] [PubMed] [Google Scholar]
  12. Cann A. J., Churcher M. J., Boyd M., O'Brien W., Zhao J. Q., Zack J., Chen I. S. The region of the envelope gene of human immunodeficiency virus type 1 responsible for determination of cell tropism. J Virol. 1992 Jan;66(1):305–309. doi: 10.1128/jvi.66.1.305-309.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Cheng-Mayer C., Levy J. A. Distinct biological and serological properties of human immunodeficiency viruses from the brain. Ann Neurol. 1988;23 (Suppl):S58–S61. doi: 10.1002/ana.410230716. [DOI] [PubMed] [Google Scholar]
  14. Cheng-Mayer C., Seto D., Levy J. A. Altered host range of HIV-1 after passage through various human cell types. Virology. 1991 Mar;181(1):288–294. doi: 10.1016/0042-6822(91)90494-v. [DOI] [PubMed] [Google Scholar]
  15. Collman R., Hassan N. F., Walker R., Godfrey B., Cutilli J., Hastings J. C., Friedman H., Douglas S. D., Nathanson N. Infection of monocyte-derived macrophages with human immunodeficiency virus type 1 (HIV-1). Monocyte-tropic and lymphocyte-tropic strains of HIV-1 show distinctive patterns of replication in a panel of cell types. J Exp Med. 1989 Oct 1;170(4):1149–1163. doi: 10.1084/jem.170.4.1149. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Dutko F. J., Oldstone M. B. Genomic and biological variation among commonly used lymphocytic choriomeningitis virus strains. J Gen Virol. 1983 Aug;64(Pt 8):1689–1698. doi: 10.1099/0022-1317-64-8-1689. [DOI] [PubMed] [Google Scholar]
  17. Epstein L. G., Kuiken C., Blumberg B. M., Hartman S., Sharer L. R., Clement M., Goudsmit J. HIV-1 V3 domain variation in brain and spleen of children with AIDS: tissue-specific evolution within host-determined quasispecies. Virology. 1991 Feb;180(2):583–590. doi: 10.1016/0042-6822(91)90072-j. [DOI] [PubMed] [Google Scholar]
  18. Gilden D. H., Cole G. A., Monjan A. A., Nathanson N. Immunopathogenesis of acute central nervous system disease produced by lymphocytic choriomeningitis virus. I. Cyclophosphamide-mediated induction by the virus-carrier state in adult mice. J Exp Med. 1972 Apr 1;135(4):860–873. doi: 10.1084/jem.135.4.860. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Jamieson B. D., Ahmed R. T-cell tolerance: exposure to virus in utero does not cause a permanent deletion of specific T cells. Proc Natl Acad Sci U S A. 1988 Apr;85(7):2265–2268. doi: 10.1073/pnas.85.7.2265. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Jamieson B. D., Somasundaram T., Ahmed R. Abrogation of tolerance to a chronic viral infection. J Immunol. 1991 Nov 15;147(10):3521–3529. [PubMed] [Google Scholar]
  21. King C. C., Jamieson B. D., Reddy K., Bali N., Concepcion R. J., Ahmed R. Viral infection of the thymus. J Virol. 1992 May;66(5):3155–3160. doi: 10.1128/jvi.66.5.3155-3160.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. King C. C., de Fries R., Kolhekar S. R., Ahmed R. In vivo selection of lymphocyte-tropic and macrophage-tropic variants of lymphocytic choriomeningitis virus during persistent infection. J Virol. 1990 Nov;64(11):5611–5616. doi: 10.1128/jvi.64.11.5611-5616.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Koyanagi Y., Miles S., Mitsuyasu R. T., Merrill J. E., Vinters H. V., Chen I. S. Dual infection of the central nervous system by AIDS viruses with distinct cellular tropisms. Science. 1987 May 15;236(4803):819–822. doi: 10.1126/science.3646751. [DOI] [PubMed] [Google Scholar]
  24. Li Q. X., Young L. S., Niedobitek G., Dawson C. W., Birkenbach M., Wang F., Rickinson A. B. Epstein-Barr virus infection and replication in a human epithelial cell system. Nature. 1992 Mar 26;356(6367):347–350. doi: 10.1038/356347a0. [DOI] [PubMed] [Google Scholar]
  25. Matloubian M., Kolhekar S. R., Somasundaram T., Ahmed R. Molecular determinants of macrophage tropism and viral persistence: importance of single amino acid changes in the polymerase and glycoprotein of lymphocytic choriomeningitis virus. J Virol. 1993 Dec;67(12):7340–7349. doi: 10.1128/jvi.67.12.7340-7349.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Matloubian M., Somasundaram T., Kolhekar S. R., Selvakumar R., Ahmed R. Genetic basis of viral persistence: single amino acid change in the viral glycoprotein affects ability of lymphocytic choriomeningitis virus to persist in adult mice. J Exp Med. 1990 Oct 1;172(4):1043–1048. doi: 10.1084/jem.172.4.1043. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Mellon P. L., Windle J. J., Goldsmith P. C., Padula C. A., Roberts J. L., Weiner R. I. Immortalization of hypothalamic GnRH neurons by genetically targeted tumorigenesis. Neuron. 1990 Jul;5(1):1–10. doi: 10.1016/0896-6273(90)90028-e. [DOI] [PubMed] [Google Scholar]
  28. Mims C. A. Immunofluorescence study of the carrier state and mechanism of vertical transmission in lymphocytic choriomeningitis virus infection in mice. J Pathol Bacteriol. 1966 Apr;91(2):395–402. doi: 10.1002/path.1700910214. [DOI] [PubMed] [Google Scholar]
  29. Moskophidis D., Lechner F., Pircher H., Zinkernagel R. M. Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells. Nature. 1993 Apr 22;362(6422):758–761. doi: 10.1038/362758a0. [DOI] [PubMed] [Google Scholar]
  30. Mucke L., Oldstone M. B. The expression of major histocompatibility complex (MHC) class I antigens in the brain differs markedly in acute and persistent infections with lymphocytic choriomeningitis virus (LCMV). J Neuroimmunol. 1992 Feb;36(2-3):193–198. doi: 10.1016/0165-5728(92)90050-U. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Oldstone M. B. Molecular anatomy of viral persistence. J Virol. 1991 Dec;65(12):6381–6386. doi: 10.1128/jvi.65.12.6381-6386.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Oldstone M. B., Salvato M., Tishon A., Lewicki H. Virus-lymphocyte interactions. III. Biologic parameters of a virus variant that fails to generate CTL and establishes persistent infection in immunocompetent hosts. Virology. 1988 Jun;164(2):507–516. doi: 10.1016/0042-6822(88)90565-x. [DOI] [PubMed] [Google Scholar]
  33. Oldstone M. B. Viral persistence. Cell. 1989 Feb 24;56(4):517–520. doi: 10.1016/0092-8674(89)90573-4. [DOI] [PubMed] [Google Scholar]
  34. Peden K., Emerman M., Montagnier L. Changes in growth properties on passage in tissue culture of viruses derived from infectious molecular clones of HIV-1LAI, HIV-1MAL, and HIV-1ELI. Virology. 1991 Dec;185(2):661–672. doi: 10.1016/0042-6822(91)90537-l. [DOI] [PubMed] [Google Scholar]
  35. Pircher H., Bürki K., Lang R., Hengartner H., Zinkernagel R. M. Tolerance induction in double specific T-cell receptor transgenic mice varies with antigen. Nature. 1989 Nov 30;342(6249):559–561. doi: 10.1038/342559a0. [DOI] [PubMed] [Google Scholar]
  36. Popescu M., Lehmann-Grube F. Diversity of lymphocytic choriomeningitis virus: variation due to replication of the virus in the mouse. J Gen Virol. 1976 Jan;30(1):113–122. doi: 10.1099/0022-1317-30-1-113. [DOI] [PubMed] [Google Scholar]
  37. Rickinson A. B., Young L. S., Rowe M. Influence of the Epstein-Barr virus nuclear antigen EBNA 2 on the growth phenotype of virus-transformed B cells. J Virol. 1987 May;61(5):1310–1317. doi: 10.1128/jvi.61.5.1310-1317.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Rodriguez M., Buchmeier M. J., Oldstone M. B., Lampert P. W. Ultrastructural localization of viral antigens in the CNS of mice persistently infected with lymphocytic choriomeningitis virus (LCMV). Am J Pathol. 1983 Jan;110(1):95–100. [PMC free article] [PubMed] [Google Scholar]
  39. Salvato M., Borrow P., Shimomaye E., Oldstone M. B. Molecular basis of viral persistence: a single amino acid change in the glycoprotein of lymphocytic choriomeningitis virus is associated with suppression of the antiviral cytotoxic T-lymphocyte response and establishment of persistence. J Virol. 1991 Apr;65(4):1863–1869. doi: 10.1128/jvi.65.4.1863-1869.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Salvato M., Shimomaye E., Southern P., Oldstone M. B. Virus-lymphocyte interactions. IV. Molecular characterization of LCMV Armstrong (CTL+) small genomic segment and that of its variant, Clone 13 (CTL-). Virology. 1988 Jun;164(2):517–522. doi: 10.1016/0042-6822(88)90566-1. [DOI] [PubMed] [Google Scholar]
  41. Sharma D. P., Zink M. C., Anderson M., Adams R., Clements J. E., Joag S. V., Narayan O. Derivation of neurotropic simian immunodeficiency virus from exclusively lymphocytetropic parental virus: pathogenesis of infection in macaques. J Virol. 1992 Jun;66(6):3550–3556. doi: 10.1128/jvi.66.6.3550-3556.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Sharpless N. E., O'Brien W. A., Verdin E., Kufta C. V., Chen I. S., Dubois-Dalcq M. Human immunodeficiency virus type 1 tropism for brain microglial cells is determined by a region of the env glycoprotein that also controls macrophage tropism. J Virol. 1992 Apr;66(4):2588–2593. doi: 10.1128/jvi.66.4.2588-2593.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Sharpless N., Gilbert D., Vandercam B., Zhou J. M., Verdin E., Ronnett G., Friedman E., Dubois-Dalcq M. The restricted nature of HIV-1 tropism for cultured neural cells. Virology. 1992 Dec;191(2):813–825. doi: 10.1016/0042-6822(92)90257-p. [DOI] [PubMed] [Google Scholar]
  44. Shioda T., Levy J. A., Cheng-Mayer C. Macrophage and T cell-line tropisms of HIV-1 are determined by specific regions of the envelope gp120 gene. Nature. 1991 Jan 10;349(6305):167–169. doi: 10.1038/349167a0. [DOI] [PubMed] [Google Scholar]
  45. Singh M. K., Fuller-Pace F. V., Buchmeier M. J., Southern P. J. Analysis of the genomic L RNA segment from lymphocytic choriomeningitis virus. Virology. 1987 Dec;161(2):448–456. doi: 10.1016/0042-6822(87)90138-3. [DOI] [PubMed] [Google Scholar]
  46. Southern P. J., Singh M. K., Riviere Y., Jacoby D. R., Buchmeier M. J., Oldstone M. B. Molecular characterization of the genomic S RNA segment from lymphocytic choriomeningitis virus. Virology. 1987 Mar;157(1):145–155. doi: 10.1016/0042-6822(87)90323-0. [DOI] [PubMed] [Google Scholar]
  47. Steuler H., Storch-Hagenlocher B., Wildemann B. Distinct populations of human immunodeficiency virus type 1 in blood and cerebrospinal fluid. AIDS Res Hum Retroviruses. 1992 Jan;8(1):53–59. doi: 10.1089/aid.1992.8.53. [DOI] [PubMed] [Google Scholar]
  48. WILSNACK R. E., ROWE W. P. IMMUNOFLUORESCENT STUDIES OF THE HISTOPATHOGENESIS OF LYMPHOCYTIC CHORIOMENINGITIS VIRUS INFECTION. J Exp Med. 1964 Nov 1;120:829–840. doi: 10.1084/jem.120.5.829. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Wu-Hsieh B., Howard D. H., Ahmed R. Virus-induced immunosuppression: a murine model of susceptibility to opportunistic infection. J Infect Dis. 1988 Jul;158(1):232–235. doi: 10.1093/infdis/158.1.232. [DOI] [PubMed] [Google Scholar]

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

RESOURCES