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. 1996 Nov;70(11):7462–7470. doi: 10.1128/jvi.70.11.7462-7470.1996

Infectivities of human and other primate lentiviruses are activated by desialylation of the virion surface.

H Hu 1, T Shioda 1, C Moriya 1, X Xin 1, M K Hasan 1, K Miyake 1, T Shimada 1, Y Nagai 1
PMCID: PMC190813  PMID: 8892864

Abstract

The envelope protein, gp120, of human immunodeficiency virus type 1 (HIV-1) is heavily glycosylated and sialylated. The heavy sialylation greatly affects the physical properties of the protein, as it resolves into a wide acidic pH range despite the basic pI value predicted for its polypeptide backbone (B. S. Stein and E. G. Engleman, J. Biol. Chem. 265:2640-2649, 1990). However, the functional significance of the heavy sialylation remains elusive. Here, we show that desialylation of HIV-1 with neuraminidase greatly augments the initial virus-cell interaction, leading to remarkably enhanced viral replication and cytopathogenicity. This enhancement appeared to be a direct result of the removal of negatively charged sialic acids but not of the exposure of galactose residues or complement activation. Complementing these results, studies with inhibitors of mannosidase I and mannosidase II showed that the processing of HIV-1 oligosaccharides into the complex type to acquire the terminal sialic acid residues impeded the full replication capacity of the virus and that its prevention also enhanced virus replication and cytopathogenicity. Enhancement of infection by desialylation was found widely, with HIV-1 laboratory strains of different cell tropisms and primary isolates as well as HIV-2 and simian immunodeficiency virus. Thus, the sialylation catalyzed by host cell pathways appeared to reduce the infectivity of human and nonhuman primate lentiviruses. Our results further suggested that desialylation would help increase the titers of HIV-based vectors.

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Selected References

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  1. Adachi A., Gendelman H. E., Koenig S., Folks T., Willey R., Rabson A., Martin M. A. Production of acquired immunodeficiency syndrome-associated retrovirus in human and nonhuman cells transfected with an infectious molecular clone. J Virol. 1986 Aug;59(2):284–291. doi: 10.1128/jvi.59.2.284-291.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Back N. K., Smit L., De Jong J. J., Keulen W., Schutten M., Goudsmit J., Tersmette M. An N-glycan within the human immunodeficiency virus type 1 gp120 V3 loop affects virus neutralization. Virology. 1994 Mar;199(2):431–438. doi: 10.1006/viro.1994.1141. [DOI] [PubMed] [Google Scholar]
  3. Benjouad A., Mabrouk K., Gluckman J. C., Fenouillet E. Effect of sialic acid removal on the antibody response to the third variable domain of human immunodeficiency virus type-1 envelope glycoprotein. FEBS Lett. 1994 Mar 21;341(2-3):244–250. doi: 10.1016/0014-5793(94)80465-6. [DOI] [PubMed] [Google Scholar]
  4. Bernstein H. B., Tucker S. P., Hunter E., Schutzbach J. S., Compans R. W. Human immunodeficiency virus type 1 envelope glycoprotein is modified by O-linked oligosaccharides. J Virol. 1994 Jan;68(1):463–468. doi: 10.1128/jvi.68.1.463-468.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Callebaut C., Krust B., Jacotot E., Hovanessian A. G. T cell activation antigen, CD26, as a cofactor for entry of HIV in CD4+ cells. Science. 1993 Dec 24;262(5142):2045–2050. doi: 10.1126/science.7903479. [DOI] [PubMed] [Google Scholar]
  6. Connor R. I., Ho D. D. Human immunodeficiency virus type 1 variants with increased replicative capacity develop during the asymptomatic stage before disease progression. J Virol. 1994 Jul;68(7):4400–4408. doi: 10.1128/jvi.68.7.4400-4408.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Corfield T. Bacterial sialidases--roles in pathogenicity and nutrition. Glycobiology. 1992 Dec;2(6):509–521. doi: 10.1093/glycob/2.6.509. [DOI] [PubMed] [Google Scholar]
  8. Doe B., Steimer K. S., Walker C. M. Induction of HIV-1 envelope (gp120)-specific cytotoxic T lymphocyte responses in mice by recombinant CHO cell-derived gp120 is enhanced by enzymatic removal of N-linked glycans. Eur J Immunol. 1994 Oct;24(10):2369–2376. doi: 10.1002/eji.1830241017. [DOI] [PubMed] [Google Scholar]
  9. Ezekowitz R. A., Kuhlman M., Groopman J. E., Byrn R. A. A human serum mannose-binding protein inhibits in vitro infection by the human immunodeficiency virus. J Exp Med. 1989 Jan 1;169(1):185–196. doi: 10.1084/jem.169.1.185. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Feizi T., Larkin M. AIDS and glycosylation. Glycobiology. 1990 Sep;1(1):17–23. doi: 10.1093/glycob/1.1.17. [DOI] [PubMed] [Google Scholar]
  11. Fennie C., Lasky L. A. Model for intracellular folding of the human immunodeficiency virus type 1 gp120. J Virol. 1989 Feb;63(2):639–646. doi: 10.1128/jvi.63.2.639-646.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Geyer H., Holschbach C., Hunsmann G., Schneider J. Carbohydrates of human immunodeficiency virus. Structures of oligosaccharides linked to the envelope glycoprotein 120. J Biol Chem. 1988 Aug 25;263(24):11760–11767. [PubMed] [Google Scholar]
  13. Gruters R. A., Neefjes J. J., Tersmette M., de Goede R. E., Tulp A., Huisman H. G., Miedema F., Ploegh H. L. Interference with HIV-induced syncytium formation and viral infectivity by inhibitors of trimming glucosidase. Nature. 1987 Nov 5;330(6143):74–77. doi: 10.1038/330074a0. [DOI] [PubMed] [Google Scholar]
  14. Kanda T., Shibuta H. A temperature-sensitive mutant of Sendai virus which establishes persistent infection in Vero cells without cell crisis. Virology. 1981 Jan 30;108(2):318–324. doi: 10.1016/0042-6822(81)90440-2. [DOI] [PubMed] [Google Scholar]
  15. Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
  16. Leonard C. K., Spellman M. W., Riddle L., Harris R. J., Thomas J. N., Gregory T. J. Assignment of intrachain disulfide bonds and characterization of potential glycosylation sites of the type 1 recombinant human immunodeficiency virus envelope glycoprotein (gp120) expressed in Chinese hamster ovary cells. J Biol Chem. 1990 Jun 25;265(18):10373–10382. [PubMed] [Google Scholar]
  17. Manca F. Galactose receptors and presentation of HIV envelope glycoprotein to specific human T cells. J Immunol. 1992 Apr 1;148(7):2278–2282. [PubMed] [Google Scholar]
  18. Meindl P., Bodo G., Palese P., Schulman J., Tuppy H. Inhibition of neuraminidase activity by derivatives of 2-deoxy-2,3-dehydro-N-acetylneuraminic acid. Virology. 1974 Apr;58(2):457–463. doi: 10.1016/0042-6822(74)90080-4. [DOI] [PubMed] [Google Scholar]
  19. Mizuochi T., Spellman M. W., Larkin M., Solomon J., Basa L. J., Feizi T. Carbohydrate structures of the human-immunodeficiency-virus (HIV) recombinant envelope glycoprotein gp120 produced in Chinese-hamster ovary cells. Biochem J. 1988 Sep 1;254(2):599–603. doi: 10.1042/bj2540599. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Mizuochi T., Spellman M. W., Larkin M., Solomon J., Basa L. J., Feizi T. Structural characterization by chromatographic profiling of the oligosaccharides of human immunodeficiency virus (HIV) recombinant envelope glycoprotein gp120 produced in Chinese hamster ovary cells. Biomed Chromatogr. 1988 Nov;2(6):260–270. doi: 10.1002/bmc.1130020608. [DOI] [PubMed] [Google Scholar]
  21. Montefiori D. C., Robinson W. E., Jr, Mitchell W. M. Antibody-independent, complement-mediated enhancement of HIV-1 infection by mannosidase I and II inhibitors. Antiviral Res. 1989 Apr;11(3):137–146. doi: 10.1016/0166-3542(89)90025-9. [DOI] [PubMed] [Google Scholar]
  22. Montefiori D. C., Robinson W. E., Jr, Mitchell W. M. Role of protein N-glycosylation in pathogenesis of human immunodeficiency virus type 1. Proc Natl Acad Sci U S A. 1988 Dec;85(23):9248–9252. doi: 10.1073/pnas.85.23.9248. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Montefiori D. C., Stewart K., Ahearn J. M., Zhou J., Zhou J. Complement-mediated binding of naturally glycosylated and glycosylation-modified human immunodeficiency virus type 1 to human CR2 (CD21). J Virol. 1993 May;67(5):2699–2706. doi: 10.1128/jvi.67.5.2699-2706.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Naidu Y. M., Kestler H. W., 3rd, Li Y., Butler C. V., Silva D. P., Schmidt D. K., Troup C. D., Sehgal P. K., Sonigo P., Daniel M. D. Characterization of infectious molecular clones of simian immunodeficiency virus (SIVmac) and human immunodeficiency virus type 2: persistent infection of rhesus monkeys with molecularly cloned SIVmac. J Virol. 1988 Dec;62(12):4691–4696. doi: 10.1128/jvi.62.12.4691-4696.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Nishikawa K., Morishima T., Toyoda T., Miyadai T., Yokochi T., Yoshida T., Nagai Y. Topological and operational delineation of antigenic sites on the HN glycoprotein of Newcastle disease virus and their structural requirements. J Virol. 1986 Dec;60(3):987–993. doi: 10.1128/jvi.60.3.987-993.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Pal R., Hoke G. M., Sarngadharan M. G. Role of oligosaccharides in the processing and maturation of envelope glycoproteins of human immunodeficiency virus type 1. Proc Natl Acad Sci U S A. 1989 May;86(9):3384–3388. doi: 10.1073/pnas.86.9.3384. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Ray P. K. Bacterial neuraminidase and altered immunological behavior of treated mammalian cells. Adv Appl Microbiol. 1977;21:227–267. doi: 10.1016/s0065-2164(08)70043-1. [DOI] [PubMed] [Google Scholar]
  28. Roggentin P., Schauer R., Hoyer L. L., Vimr E. R. The sialidase superfamily and its spread by horizontal gene transfer. Mol Microbiol. 1993 Sep;9(5):915–921. doi: 10.1111/j.1365-2958.1993.tb01221.x. [DOI] [PubMed] [Google Scholar]
  29. Shibata R., Miura T., Hayami M., Ogawa K., Sakai H., Kiyomasu T., Ishimoto A., Adachi A. Mutational analysis of the human immunodeficiency virus type 2 (HIV-2) genome in relation to HIV-1 and simian immunodeficiency virus SIV (AGM). J Virol. 1990 Feb;64(2):742–747. doi: 10.1128/jvi.64.2.742-747.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Shimada T., Fujii H., Mitsuya H., Nienhuis A. W. Targeted and highly efficient gene transfer into CD4+ cells by a recombinant human immunodeficiency virus retroviral vector. J Clin Invest. 1991 Sep;88(3):1043–1047. doi: 10.1172/JCI115365. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. 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]
  32. Stein B. S., Engleman E. G. Intracellular processing of the gp160 HIV-1 envelope precursor. Endoproteolytic cleavage occurs in a cis or medial compartment of the Golgi complex. J Biol Chem. 1990 Feb 15;265(5):2640–2649. [PubMed] [Google Scholar]
  33. Vimr E. R. Microbial sialidases: does bigger always mean better? Trends Microbiol. 1994 Aug;2(8):271–277. doi: 10.1016/0966-842x(94)90003-5. [DOI] [PubMed] [Google Scholar]
  34. Willey R. L., Smith D. H., Lasky L. A., Theodore T. S., Earl P. L., Moss B., Capon D. J., Martin M. A. In vitro mutagenesis identifies a region within the envelope gene of the human immunodeficiency virus that is critical for infectivity. J Virol. 1988 Jan;62(1):139–147. doi: 10.1128/jvi.62.1.139-147.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]

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