1887

Abstract

Human immunodeficiency virus type 1 (HIV-1) resistance to broadly neutralizing antibodies such as b12, which targets the highly conserved CD4-binding site, raises a significant hurdle for the development of a neutralizing antibody-based vaccine. Here, 15 individuals were studied of whom seven developed b12-resistant viruses late in infection. The study investigated whether immune pressure may be involved in the selection of these viruses . Although four out of seven patients showed HIV-1-specific broadly neutralizing activity in serum, none of these patients had CD4-binding site-directed antibodies, indicating that strong humoral immunity is not a prerequisite for the outgrowth of b12-resistant viruses. In virus variants from one patient, who showed extremely weak heterologous and autologous neutralizing activity in serum, mutations were identified in the envelope that coincided with changes in b12 neutralization sensitivity. Lack of cytotoxic T-cell activity against epitopes with and without these mutations excluded a role for host cellular immunity in the selection of b12-resistant mutant viruses in this patient. However, b12 resistance correlated well with increased virus replication kinetics, indicating that selection for enhanced infectivity, possibly driven by the low availability of target cells in the later stages of disease, may coincide with increased resistance to CD4-binding site-directed agents, such as b12. These results showed that b12-resistant HIV-1 variants can emerge during the course of natural infection in the absence of both humoral and cellular immune pressure, suggestive of other mechanisms playing a role in the selective outgrowth of b12-resistant viruses.

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2010-05-01
2019-11-18
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References

  1. Beaumont, T., van Nuenen, A., Broersen, S., Blattner, W. A., Lukashov, V. V. & Schuitemaker, H. ( 2001; ). Reversal of HIV-1 IIIB towards a neutralization resistant phenotype in an accidentally infected laboratory worker with a progressive clinical course. J Virol 75, 2246–2252.[CrossRef]
    [Google Scholar]
  2. Beaumont, T., Quakkelaar, E., van Nuenen, A., Pantophlet, R. & Schuitemaker, H. ( 2004; ). Increased sensitivity to CD4 binding site-directed neutralization following in vitro propagation on primary lymphocytes of a neutralization-resistant human immunodeficiency virus IIIB strain isolated from an accidentally infected laboratory worker. J Virol 78, 5651–5657.[CrossRef]
    [Google Scholar]
  3. Binley, J. M., Wrin, T., Korber, B., Zwick, M. B., Wang, M., Chappey, C., Stiegler, G., Kunert, R., Zolla-Pazner, S. & other authors ( 2004; ). Comprehensive cross-clade neutralization analysis of a panel of anti-human immunodeficiency virus type 1 monoclonal antibodies. J Virol 78, 13232–13252.[CrossRef]
    [Google Scholar]
  4. Boom, R., Sol, C. J. A., Salimans, M. M. M., Jansen, C. L., Wertheim-van Dillen, P. M. E. & van der Noordaa, J. ( 1991; ). Rapid and simple method for purification of nucleic acids. J Clin Microbiol 28, 495–503.
    [Google Scholar]
  5. Bunnik, E. M., Pisas, L., van Nuenen, A. C. & Schuitemaker, H. ( 2008; ). Autologous neutralizing humoral immunity and evolution of the viral envelope in the course of subtype B human immunodeficiency virus type 1 infection. J Virol 82, 7932–7941.[CrossRef]
    [Google Scholar]
  6. Bunnik, E. M., van Gils, M. J., Lobbrecht, M. S., Pisas, L., van Nuenen, A. C. & Schuitemaker, H. ( 2009; ). Changing sensitivity to broadly neutralizing antibodies b12, 2G12, 2F5, and 4E10 of primary subtype B human immunodeficiency virus type 1 variants in the natural course of infection. Virology 390, 348–355.[CrossRef]
    [Google Scholar]
  7. Burton, D. R. ( 2002; ). Antibodies, viruses and vaccines. Nat Rev Immunol 2, 706–713.[CrossRef]
    [Google Scholar]
  8. Burton, D. R., Pyati, J., Koduri, R., Sharp, S. J., Thornton, G. B., Parren, P. W. H., Sawyer, L. S. W., Hendry, R. M., Dunlop, N. & other authors ( 1994; ). Efficient neutralization of primary isolates of HIV-1 by a recombinant human monoclonal antibody. Science 266, 1024–1027.[CrossRef]
    [Google Scholar]
  9. Burton, D. R., Desrosiers, R. C., Doms, R. W., Koff, W. C., Kwong, P. D., Moore, J. P., Nabel, G. J., Sodroski, J., Wilson, I. A. & other authors ( 2004; ). HIV vaccine design and the neutralizing antibody problem. Nat Immunol 5, 233–236.[CrossRef]
    [Google Scholar]
  10. Chen, B., Vogan, E. M., Gong, H., Skehel, J. J., Wiley, D. C. & Harrison, S. C. ( 2005; ). Structure of an unliganded simian immunodeficiency virus gp120 core. Nature 433, 834–841.[CrossRef]
    [Google Scholar]
  11. Decker, J. M., Bibollet-Ruche, F., Wei, X., Wang, S., Levy, D. N., Wang, W., Delaporte, E., Peeters, M., Derdeyn, C. A. & other authors ( 2005; ). Antigenic conservation and immunogenicity of the HIV coreceptor binding site. J Exp Med 201, 1407–1419.[CrossRef]
    [Google Scholar]
  12. Desrosiers, R. C. ( 2004; ). Prospects for an AIDS vaccine. Nat Med 10, 221–223.[CrossRef]
    [Google Scholar]
  13. Duenas-Decamp, M. J., Peters, P., Burton, D. & Clapham, P. R. ( 2008; ). Natural resistance of human immunodeficiency virus type 1 to the CD4bs antibody b12 conferred by a glycan and an arginine residue close to the CD4 binding loop. J Virol 82, 5807–5814.[CrossRef]
    [Google Scholar]
  14. Duenas-Decamp, M. J., Peters, P. J., Burton, D. & Clapham, P. R. ( 2009; ). Determinants flanking the CD4 binding loop modulate macrophage tropism of human immunodeficiency virus type 1 R5 envelopes. J Virol 83, 2575–2583.[CrossRef]
    [Google Scholar]
  15. Edwards, T. G., Hoffman, T. L., Baribaud, F., Wyss, S., LaBranche, C. C., Romano, J., Adkinson, J., Sharron, M., Hoxie, J. A. & other authors ( 2001; ). Relationships between CD4 independence, neutralization sensitivity, and exposure of a CD4-induced epitope in a human immunodeficiency virus type 1 envelope protein. J Virol 75, 5230–5239.[CrossRef]
    [Google Scholar]
  16. Euler, Z., van Gils, M. J., Bunnik, E. M., Phung, P., Schweighardt, B., Wrin, T. & Schuitemaker, H. ( 2010; ). Cross-reactive neutralizing humoral immunity does not protect from HIV-1 disease progression. J Infect Dis 201, 981–983.[CrossRef]
    [Google Scholar]
  17. Gray, L., Sterjovski, J., Churchill, M., Ellery, P., Nasr, N., Lewin, S. R., Crowe, S. M., Wesselingh, S. L., Cunningham, A. L. & other authors ( 2005; ). Uncoupling coreceptor usage of human immunodeficiency virus type 1 (HIV-1) from macrophage tropism reveals biological properties of CCR5-restricted HIV-1 isolates from patients with acquired immunodeficiency syndrome. Virology 337, 384–398.[CrossRef]
    [Google Scholar]
  18. Greenhead, P., Hayes, P., Watts, P. S., Laing, K. G., Griffin, G. E. & Shattock, R. J. ( 2000; ). Parameters of human immunodeficiency virus infection of human cervical tissue and inhibition by vaginal virucides. J Virol 74, 5577–5586.[CrossRef]
    [Google Scholar]
  19. Hall, T. A. ( 1999; ). BioEdit: a user-friendly biological sequence alignment editor and analysis program for Windows 95/98/NT. Nucleic Acids Symp Ser 41, 95–98.
    [Google Scholar]
  20. Hogan, C. M. & Hammer, S. M. ( 2001; ). Host determinants in HIV infection and disease. Part 2: genetic factors and implications for antiretroviral therapeutics. Ann Intern Med 134, 978–996.[CrossRef]
    [Google Scholar]
  21. Jensen, M. A., Li, F. S., Van 't Wout, A. B., Nickle, D. C., Shriner, D., He, H. X., McLaughlin, S., Shankarappa, R., Margolick, J. B. & other authors ( 2003; ). Improved coreceptor 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]
  22. Kaslow, R. A., Carrington, M., Apple, R., Park, L., Muñoz, A., Saah, A. J., Goedert, J. J., Winkler, C., O'Brien, S. J. & other authors ( 1996; ). Influence of combinations of human major histocompatibility complex genes on the course of HIV-1 infection. Nat Med 2, 405–411.[CrossRef]
    [Google Scholar]
  23. Keele, B. F., Giorgi, E. E., Salazar-Gonzalez, J. F., Decker, J. M., Pham, K. T., Salazar, M. G., Sun, C., Grayson, T., Wang, S. & other authors ( 2008; ). Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection. Proc Natl Acad Sci U S A 105, 7552–7557.[CrossRef]
    [Google Scholar]
  24. Koning, F. A., Kwa, D., Boeser-Nunnink, B., Dekker, J., Vingerhoed, J., Hiemstra, H. & Schuitemaker, H. ( 2003; ). Decreasing sensitivity to RANTES neutralization of CC chemokine receptor 5-using, non-syncytium-inducing virus variants in the course of human immunodeficiency virus type 1 infection. J Infect Dis 188, 864–872.[CrossRef]
    [Google Scholar]
  25. Kwong, P. D., Wyatt, R., Robinson, J., Sweet, R. W., Sodroski, J. & Hendrickson, W. A. ( 1998; ). Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody. Nature 393, 648–659.[CrossRef]
    [Google Scholar]
  26. Mo, H., Stamatatos, L., Ip, J. E., Barbas, C. F., Parren, P. W. H. I., Burton, D. R., Moore, J. P. & Ho, D. D. ( 1997; ). Human immunodeficiency virus type 1 mutants that escape neutralization by human monoclonal antibody IgG1b12. J Virol 71, 6869–6874.
    [Google Scholar]
  27. Muster, T., Steindl, F., Purtscher, M., Trkola, A., Klima, A., Himmler, G., Ruker, F. & Katinger, H. ( 1993; ). A conserved neutralizing epitope on gp41 of human immunodeficiency virus type 1. J Virol 67, 6642–6647.
    [Google Scholar]
  28. Pantophlet, R., Ollman Saphire, E., Poignard, P., Parren, P. W. H. I., Wilson, I. A. & Burton, D. R. ( 2003; ). Fine mapping of the interaction of neutralizing and nonneutralizing monoclonal antibodies with the CD4 binding site of human immunodeficiency virus type 1 gp120. J Virol 77, 642–658.[CrossRef]
    [Google Scholar]
  29. Peden, K., Emerman, M. & Montagnier, L. ( 1991; ). 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 185, 661–672.[CrossRef]
    [Google Scholar]
  30. Peters, P. J., Duenas-Decamp, M. J., Sullivan, W. M., Brown, R., Ankghuambom, C., Luzuriaga, K., Robinson, J., Burton, D. R., Bell, J. & other authors ( 2008; ). Variation in HIV-1 R5 macrophage-tropism correlates with sensitivity to reagents that block envelope:  CD4 interactions but not with sensitivity to other entry inhibitors. Retrovirology 5, 5 [CrossRef]
    [Google Scholar]
  31. Petropoulos, C. J., Parkin, N. T., Limoli, K. L., Lie, Y. S., Wrin, T., Huang, W., Tian, H., Smith, D., Winslow, G. A. & other authors ( 2000; ). A novel phenotypic drug susceptibility assay for human immunodeficiency virus type 1. Antimicrob Agents Chemother 44, 920–928.[CrossRef]
    [Google Scholar]
  32. Piantadosi, A., Panteleeff, D., Blish, C. A., Baeten, J. M., Jaoko, W., McClelland, R. S. & Overbaugh, J. ( 2009; ). HIV-1 neutralizing antibody breadth is affected by factors early in infection, but does not influence disease progression. J Virol 83, 10269–10274.[CrossRef]
    [Google Scholar]
  33. Poignard, P., Sabbe, R., Picchio, G. R., Wang, M., Gulizia, R. J., Katinger, H., Parren, P. W. H. I., Mosier, D. E. & Burton, D. R. ( 1999; ). Neutralizing antibodies have limited effects on the control of established HIV-1 infection in vivo. Immunity 10, 431–438.[CrossRef]
    [Google Scholar]
  34. Quakkelaar, E. D., Bunnik, E. M., van Alphen, F. P., Boeser-Nunnink, B. D., van Nuenen, A. C. & Schuitemaker, H. ( 2007a; ). Escape of human immunodeficiency virus type 1 from broadly neutralizing antibodies is not associated with a reduction of viral replicative capacity in vitro. Virology 363, 447–453.[CrossRef]
    [Google Scholar]
  35. Quakkelaar, E. D., van Alphen, F. P., Boeser-Nunnink, B. D., van Nuenen, A. C., Pantophlet, R. & Schuitemaker, H. ( 2007b; ). Susceptibility of recently transmitted subtype B human immunodeficiency virus type 1 variants to broadly neutralizing antibodies. J Virol 81, 8533–8542.[CrossRef]
    [Google Scholar]
  36. Repits, J., Sterjovski, J., Badia-Martinez, D., Mild, M., Gray, L., Churchill, M. J., Purcell, D. F., Karlsson, A., Albert, J. & other authors ( 2008; ). Primary HIV-1 R5 isolates from end-stage disease display enhanced viral fitness in parallel with increased gp120 net charge. Virology 379, 125–134.[CrossRef]
    [Google Scholar]
  37. Richman, D. D., Wrin, T., Little, S. J. & Petropoulos, C. J. ( 2003; ). Rapid evolution of the neutralizing antibody response to HIV type 1 infection. Proc Natl Acad Sci U S A 100, 4144–4149.[CrossRef]
    [Google Scholar]
  38. Rusert, P., Kuster, H., Joos, B., Misselwitz, B., Gujer, C., Leemann, C., Fischer, M., Stiegler, G., Katinger, H. & other authors ( 2005; ). Virus isolates during acute and chronic human immunodeficiency virus type 1 infection show distinct patterns of sensitivity to entry inhibitors. J Virol 79, 8454–8469.[CrossRef]
    [Google Scholar]
  39. Saphire, E. O., Parren, P. W., Pantophlet, R., Zwick, M. B., Morris, G. M., Rudd, P. M., Dwek, R. A., Stanfield, R. L., Burton, D. R. & other authors ( 2001; ). Crystal structure of a neutralizing human IgG against HIV-1: a template for vaccine design. Science 293, 1155–1159.[CrossRef]
    [Google Scholar]
  40. Schuitemaker, H., Koot, M., Kootstra, N. A., Dercksen, M. W., De Goede, R. E. Y., Van Steenwijk, R. P., Lange, J. M. A., Eeftink Schattenkerk, J. K. M., Miedema, F. & other authors ( 1992; ). Biological phenotype of human immunodeficiency virus type 1 clones at different stages of infection: progression of disease is associated with a shift from monocytotropic to T-cell-tropic virus populations. J Virol 66, 1354–1360.
    [Google Scholar]
  41. Schweighardt, B., Liu, Y., Huang, W., Chappey, C., Lie, Y. S., Petropoulos, C. J. & Wrin, T. ( 2007; ). Development of an HIV-1 reference panel of subtype B envelope clones isolated from the plasma of recently infected individuals. J Acquir Immune Defic Syndr 46, 1–11.[CrossRef]
    [Google Scholar]
  42. Stiegler, G., Kunert, R., Purtscher, M., Wolbank, S., Voglauer, R., Steindl, F. & Katinger, H. ( 2001; ). A potent cross-clade neutralizing human monoclonal antibody against a novel epitope on gp41 of human immunodeficiency virus type 1. AIDS Res Hum Retroviruses 17, 1757–1765.[CrossRef]
    [Google Scholar]
  43. Tersmette, M., Winkel, I. N., Groenink, M., Gruters, R. A., Spence, P., Saman, E., van der Groen, G., Miedema, F. & Huisman, J. G. ( 1989; ). Detection and subtyping of HIV-1 isolates with a panel of characterized monoclonal antibodies to HIV-p24 gag . Virology 171, 149–155.[CrossRef]
    [Google Scholar]
  44. Trkola, A., Pomales, A. B., Yuan, H., Korber, B., Maddon, P. J., Allaway, G. P., Katinger, H., Barbas, C. F., III, Burton, D. R. & other authors ( 1995; ). Cross-clade neutralization of primary isolates of human immunodeficiency virus type 1 by human monoclonal antibodies and tetrameric CD4–IgG. J Virol 69, 6609–6617.
    [Google Scholar]
  45. van Gils, M. J., Euler, Z., Schweighardt, B., Wrin, T. & Schuitemaker, H. ( 2009; ). Prevalence of cross-reactive HIV-1-neutralizing activity in HIV-1-infected patients with rapid or slow disease progression. AIDS 23, 2405–2414.[CrossRef]
    [Google Scholar]
  46. van Griensven, G. J. P., de Vroome, E. M. M., Goudsmit, J. & Coutinho, R. A. ( 1989; ). Changes in sexual behaviour and the fall in incidence of HIV infection among homosexual men. BMJ 298, 218–221.[CrossRef]
    [Google Scholar]
  47. Van't Wout, A. B., Kootstra, N. A., Mulder-Kampinga, G. A., Albrecht-van Lent, N., Scherpbier, H. J., Veenstra, J., Boer, K., Coutinho, R. A., Miedema, F. & Schuitemaker, H. ( 1994; ). Macrophage-tropic variants initiate human immunodeficiency virus type 1 infection after sexual, parenteral, and vertical transmission. J Clin Invest 94, 2060–2067.[CrossRef]
    [Google Scholar]
  48. Van't Wout, A. B., Schuitemaker, H. & Kootstra, N. A. ( 2008; ). Isolation and propagation of HIV-1 on peripheral blood mononuclear cells. Nat Protoc 3, 363–370.[CrossRef]
    [Google Scholar]
  49. Wu, X., Zhou, T., O'Dell, S., Wyatt, R. T., Kwong, P. D. & Mascola, J. R. ( 2009; ). Mechanism of HIV-1 resistance to monoclonal antibody b12 that effectively targets the site of CD4 attachment. J Virol 83, 10892–10907.[CrossRef]
    [Google Scholar]
  50. Wyatt, R., Kwong, P. D., Desjardins, E., Sweet, R. W., Robinson, J., Hendrickson, W. A. & Sodroski, J. ( 1998; ). The antigenic structure of the HIV gp120 envelope protein. Nature 393, 705–711.[CrossRef]
    [Google Scholar]
  51. Zhou, T., Xu, L., Dey, B., Hessell, A. J., Van Ryk, D., Xiang, S. H., Yang, X., Zhang, M. Y., Zwick, M. B. & other authors ( 2007; ). Structural definition of a conserved neutralization epitope on HIV-1 gp120. Nature 445, 732–737.[CrossRef]
    [Google Scholar]
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vol. , part 5, pp. 1354–1364

Sensitivity for neutralization by mAbs 2G12, 2F5 and 4E10 of longitudinally obtained virus variants from patients H6, H7, H8 and H9 [ PDF] (158 KB)



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