1887

Abstract

Human immunodeficiency virus type 1 (HIV-1) enters cells through the chemokine receptors CCR5 (R5 virus) and/or CXCR4 (X4 virus). Loss of -linked glycans and increased net charge of the third variable loop (V3) of the gp120 envelope glycoprotein have been observed to be important steps towards CXCR4 use. All reported sequences using CCR5 or CXCR4 exclusively, or using both, were gathered from the Los Alamos HIV Database and analysed with regard to the V3 -linked glycosylation motifs (sequons) and charge. The V3 loop glycan had a sensitivity of 0·98 and a 0·92 positive predictive value in the context of CCR5 use. The difference from X4 was remarkable (<10). Especially, the sequon motif NNT within the V3 loop was conserved in 99·2 % of the major clades. The results suggest a close association between the V3 loop glycan and CCR5 use and may provide new insight into HIV-1 tropism and help to improve phenotype-prediction models.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.81510-0
2006-03-01
2019-11-18
Loading full text...

Full text loading...

/deliver/fulltext/jgv/87/3/607.html?itemId=/content/journal/jgv/10.1099/vir.0.81510-0&mimeType=html&fmt=ahah

References

  1. Berger, E. A., Doms, R. W., Fenyö, E.-M. & 7 other authors ( 1998; ). A new classification for HIV-1. Nature 391, 240.[CrossRef]
    [Google Scholar]
  2. Brelot, A., Heveker, N., Adema, K., Hosie, M. J., Willett, B. & Alizon, M. ( 1999; ). Effect of mutations in the second extracellular loop of CXCR4 on its utilization by human and feline immunodeficiency viruses. J Virol 73, 2576–2586.
    [Google Scholar]
  3. Briggs, D. R., Tuttle, D. L., Sleasman, J. W. & Goodenow, M. M. ( 2000; ). Envelope V3 amino acid sequence predicts HIV-1 phenotype (co-receptor usage and tropism for macrophages). AIDS 14, 2937–2939.[CrossRef]
    [Google Scholar]
  4. Chabot, D. J. & Broder, C. C. ( 2000; ). Substitutions in a homologous region of extracellular loop 2 of CXCR4 and CCR5 alter coreceptor activities for HIV-1 membrane fusion and virus entry. J Biol Chem 275, 23774–23782.[CrossRef]
    [Google Scholar]
  5. Chabot, D. J., Chen, H., Dimitrov, D. S. & Broder, C. C. ( 2000; ). N-linked glycosylation of CXCR4 masks coreceptor function for CCR5-dependent human immunodeficiency virus type 1 isolates. J Virol 74, 4404–4413.[CrossRef]
    [Google Scholar]
  6. Clevestig, P., Maljkovic, I., Casper, C. & 7 other authors ( 2005; ). The X4 phenotype of HIV type 1 evolves from R5 in two children of mothers, carrying X4, and is not linked to transmission. AIDS Res Hum Retroviruses 21, 371–378.[CrossRef]
    [Google Scholar]
  7. Connor, R. I., Sheridan, K. E., Ceradini, D., Choe, S. & Landau, N. R. ( 1997; ). Change in coreceptor use correlates with disease progression in HIV-1-infected individuals. J Exp Med 185, 621–628.[CrossRef]
    [Google Scholar]
  8. De Jong, J.-J., De Ronde, A., Keulen, W., Tersmette, M. & Goudsmit, J. ( 1992; ). Minimal requirements for the human immunodeficiency virus type 1 V3 domain to support the syncytium-inducing phenotype: analysis by single amino acid substitution. J Virol 66, 6777–6780.
    [Google Scholar]
  9. De Wolf, F., Hogervorst, E., Goudsmit, J. & 52 other authors ( 1994; ). Syncytium-inducing and non-syncytium-inducing capacity of human immunodeficiency virus type 1 subtypes other than B: phenotypic and genotypic characteristics. WHO Network for HIV Isolation and Characterization. AIDS Res Hum Retroviruses 10, 1387–1400.[CrossRef]
    [Google Scholar]
  10. Engelbrecht, S., de Villiers, T., Sampson, C. C., zur Megede, J., Barnett, S. W. & van Rensburg, E. J. ( 2001; ). Genetic analysis of the complete gag and env genes of HIV type 1 subtype C primary isolates from South Africa. AIDS Res Hum Retroviruses 17, 1533–1547.[CrossRef]
    [Google Scholar]
  11. Fouchier, R. A. M., Groenink, M., Kootstra, N. A., Tersmette, M., Huisman, H. G., Miedema, F. & Schuitemaker, H. ( 1992; ). Phenotype-associated sequence variation in the third variable domain of the human immunodeficiency virus type 1 gp120 molecule. J Virol 66, 3183–3187.
    [Google Scholar]
  12. Gao, F., Morrison, S. G., Robertson, D. L. & 12 other authors ( 1996; ). Molecular cloning and analysis of functional envelope genes from human immunodeficiency virus type 1 sequence subtypes A through G. The WHO and NIAID Networks for HIV Isolation and Characterization. J Virol 70, 1651–1667.
    [Google Scholar]
  13. Gavel, Y. & von Heijne, G. ( 1990; ). Sequence differences between glycosylated and non-glycosylated Asn-X-Thr/Ser acceptor sites: implications for protein engineering. Protein Eng 3, 433–442.[CrossRef]
    [Google Scholar]
  14. Hartley, O., Klasse, P. J., Sattentau, Q. J. & Moore, J. P. ( 2005; ). V3: HIV's switch-hitter. AIDS Res Hum Retroviruses 21, 171–189.[CrossRef]
    [Google Scholar]
  15. Hwang, S. S., Boyle, T. J., Lyerly, H. K. & Cullen, B. R. ( 1991; ). Identification of the envelope V3 loop as the primary determinant of cell tropism in HIV-1. Science 253, 71–74.[CrossRef]
    [Google Scholar]
  16. Jensen, M. A., Li, F.-S., van't Wout, A. B. & 7 other authors ( 2003; ). Improved co-receptor usage prediction and genotypic monitoring of R5-to-X4 transition by motif analysis of human immunodeficiency virus type 1 env V3 loop sequences. J Virol 77, 13376–13388.[CrossRef]
    [Google Scholar]
  17. Kasturi, L., Chen, H. & Shakin-Eshleman, S. H. ( 1997; ). Regulation of N-linked core glycosylation: use of a site-directed mutagenesis approach to identify Asn-Xaa-Ser/Thr sequons that are poor oligosaccharide acceptors. Biochem J 323, 415–419.
    [Google Scholar]
  18. Losman, B., Biller, M., Olofsson, S., Schønning, K., Lund, O. S., Svennerholm, B., Hansen, J.-E. S. & Bolmstedt, A. ( 1999; ). The N-linked glycan of the V3 region of HIV-1 gp120 and CXCR4-dependent multiplication of a human immunodeficiency virus type 1 lymphocyte-tropic variant. FEBS Lett 454, 47–52.[CrossRef]
    [Google Scholar]
  19. Marshall, R. D. ( 1972; ). Glycoproteins. Annu Rev Biochem 41, 673–702.[CrossRef]
    [Google Scholar]
  20. Mellquist, J. L., Kasturi, L., Spitalnik, S. L. & Shakin-Eshleman, S. H. ( 1998; ). The amino acid following an Asn-X-Ser/Thr sequon is an important determinant of N-linked core glycosylation efficiency. Biochemistry 37, 6833–6837.[CrossRef]
    [Google Scholar]
  21. Nilsson, I. & von Heijne, G. ( 2000; ). Glycosylation efficiency of Asn-Xaa-Thr sequons depends both on the distance from the C terminus and on the presence of a downstream transmembrane segment. J Biol Chem 275, 17338–17343.[CrossRef]
    [Google Scholar]
  22. Pillai, S., Good, B., Richman, D. & Corbeil, J. ( 2003; ). A new perspective on V3 phenotype prediction. AIDS Res Hum Retroviruses 19, 145–149.[CrossRef]
    [Google Scholar]
  23. Pollakis, G., Kang, S., Kliphuis, A., Chalaby, M. I. M., Goudsmit, J. & Paxton, W. A. ( 2001; ). N-Linked glycosylation of the HIV type-1 gp120 envelope glycoprotein as a major determinant of CCR5 and CXCR4 coreceptor utilization. J Biol Chem 276, 13433–13441.[CrossRef]
    [Google Scholar]
  24. Polzer, S., Dittmar, M. T., Schmitz, H., Meyer, B., Müller, H., Kräusslich, H.-G. & Schreiber, M. ( 2001; ). Loss of N-linked glycans in the V3-loop region of gp120 is correlated to an enhanced infectivity of HIV-1. Glycobiology 11, 11–19.[CrossRef]
    [Google Scholar]
  25. Polzer, S., Dittmar, M. T., Schmitz, H. & Schreiber, M. ( 2002; ). The N-linked glycan g15 within the V3 loop of the HIV-1 external glycoprotein gp120 affects coreceptor usage, cellular tropism, and neutralization. Virology 304, 70–80.[CrossRef]
    [Google Scholar]
  26. Pontow, S. & Ratner, L. ( 2001; ). Evidence for common structural determinants of human immunodeficiency virus type 1 coreceptor activity provided through functional analysis of CCR5/CXCR4 chimeric coreceptors. J Virol 75, 11503–11514.[CrossRef]
    [Google Scholar]
  27. Rambaut, A. ( 2002; ). Se-Al Sequence Alignment Program, version 2.0a11. Department of Zoology, University of Oxford, Oxford, UK.
  28. Resch, W., Hoffman, N. & Swanstrom, R. ( 2001; ). Improved success of phenotype prediction of the human immunodeficiency virus type 1 from envelope variable loop 3 sequence using neural networks. Virology 288, 51–62.[CrossRef]
    [Google Scholar]
  29. Scarlatti, G., Tresoldi, E., Björndal, Å. & 9 other authors ( 1997; ). In vivo evolution of HIV-1 co-receptor usage and sensitivity to chemokine-mediated suppression. Nat Med 3, 1259–1265.[CrossRef]
    [Google Scholar]
  30. Shakin-Eshleman, S. H., Spitalnik, S. L. & Kasturi, L. ( 1996; ). The amino acid at the X position of an Asn-X-Ser sequon is an important determinant of N-linked core-glycosylation efficiency. J Biol Chem 271, 6363–6366.[CrossRef]
    [Google Scholar]
  31. Shioda, T., Levy, J. A. & Cheng-Mayer, C. ( 1992; ). Small amino acid changes in the V3 hypervariable region of gp120 can affect the T-cell-line and macrophage tropism of human immunodeficiency virus type 1. Proc Natl Acad Sci U S A 89, 9434–9438.[CrossRef]
    [Google Scholar]
  32. Tebit, D. M., Zekeng, L., Kaptué, L., Salminen, M., Kräusslich, H.-G. & Herchenröder, O. ( 2002; ). Genotypic and phenotypic analysis of HIV type 1 primary isolates from western Cameroon. AIDS Res Hum Retroviruses 18, 39–48.[CrossRef]
    [Google Scholar]
  33. Zhang, L. Q., MacKenzie, P., Cleland, A., Holmes, E. C., Leigh Brown, A. J. & Simmonds, P. ( 1993; ). Selection for specific sequences in the external envelope protein of human immunodeficiency virus type 1 upon primary infection. J Virol 67, 3345–3356.
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.81510-0
Loading
/content/journal/jgv/10.1099/vir.0.81510-0
Loading

Data & Media loading...

Supplements

Details on retrieved sequences [ PDF file] (216 KB)

PDF

R5, X4 and dual-tropic sequence alignments [ PDF file] (51 KB)

PDF

Most Cited This Month

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error