1887

Abstract

It has been reported that the addition of a potential -linked glycosylation site (PNGS) to the gp120 human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein provides protection against neutralizing antibodies (NAbs) by acting as a ‘glycan shield’. In this study, we induced insertion of a PNGS into the V2 region of HIV-1 with the KD-247 anti-V3 neutralizing monoclonal antibody. In the presence of KD-247 (200 μg ml) at passage five, viruses with 3 aa mutations in the C2 (T240S and I283T) and V3 (T319A) regions expanded from pre-existing variants. After six passages with KD-247 (>300 μg ml), a PNGS emerged in the V2 region in addition to C2 (T240S) and V3 mutations (R315K and F317L). A variant with a PNGS insertion in V2, but no V3 mutations was sensitive to KD-247, whereas a clone with a V2 PNGS insertion and mutations in V3 demonstrated a high level of resistance to KD-247. Replication kinetic analysis revealed that the F317L mutation in V3 played a compensatory role for fitness-loss caused by the PNGS insertion in V2. The evading HIV-1 variant did not revert back to the wild-type virus after 14 passages without KD-247. These findings demonstrate that the virus with fitness-loss mutations can replicate equally as well as the wild-type virus to acquire some key mutations in the V3 stem and the C2 region, and the compensated variants containing PNGS do not revert back to the ancestral virus even in the absence of NAb.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.017426-0
2010-05-01
2019-11-19
Loading full text...

Full text loading...

/deliver/fulltext/jgv/91/5/1335.html?itemId=/content/journal/jgv/10.1099/vir.0.017426-0&mimeType=html&fmt=ahah

References

  1. Anastassopoulou, C. G., Ketas, T. J., Klasse, P. J. & Moore, J. P. ( 2009; ). Resistance to CCR5 inhibitors caused by sequence changes in the fusion peptide of HIV-1 gp41. Proc Natl Acad Sci U S A 106, 5318–5323.[CrossRef]
    [Google Scholar]
  2. Baba, M., Miyake, H., Wang, X., Okamoto, M. & Takashima, K. ( 2007; ). Isolation and characterization of human immunodeficiency virus type 1 resistant to the small-molecule CCR5 antagonist TAK-652. Antimicrob Agents Chemother 51, 707–715.[CrossRef]
    [Google Scholar]
  3. Berro, R., Sanders, R. W., Lu, M., Klasse, P. J. & Moore, J. P. ( 2009; ). Two HIV-1 variants resistant to small molecule CCR5 inhibitors differ in how they use CCR5 for entry. PLoS Pathog 5, e1000548 [CrossRef]
    [Google Scholar]
  4. Bontjer, I., Land, A., Eggink, D., Verkade, E., Tuin, K., Baldwin, C., Pollakis, G., Paxton, W. A., Braakman, I. & other authors ( 2009; ). Optimization of human immunodeficiency virus type 1 envelope glycoproteins with V1/V2 deleted, using virus evolution. J Virol 83, 368–383.[CrossRef]
    [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. Cao, Y., Qin, L., Zhang, L., Safrit, J. & Ho, D. D. ( 1995; ). Virologic and immunologic characterization of long-term survivors of human immunodeficiency virus type 1 infection. N Engl J Med 332, 201–208.[CrossRef]
    [Google Scholar]
  7. Cutalo, J. M., Deterding, L. J. & Tomer, K. B. ( 2004; ). Characterization of glycopeptides from HIV-I(SF2) gp120 by liquid chromatography mass spectrometry. J Am Soc Mass Spectrom 15, 1545–1555.[CrossRef]
    [Google Scholar]
  8. Deeks, S. G., Schweighardt, B., Wrin, T., Galovich, J., Hoh, R., Sinclair, E., Hunt, P., McCune, J. M., Martin, J. N. & other authors ( 2006; ). Neutralizing antibody responses against autologous and heterologous viruses in acute versus chronic human immunodeficiency virus (HIV) infection: evidence for a constraint on the ability of HIV to completely evade neutralizing antibody responses. J Virol 80, 6155–6164.[CrossRef]
    [Google Scholar]
  9. Eda, Y., Takizawa, M., Murakami, T., Maeda, H., Kimachi, K., Yonemura, H., Koyanagi, S., Shiosaki, K., Higuchi, H. & other authors ( 2006; ). Sequential immunization with V3 peptides from primary human immunodeficiency virus type 1 produces cross-neutralizing antibodies against primary isolates with a matching narrow-neutralization sequence motif. J Virol 80, 5552–5562.[CrossRef]
    [Google Scholar]
  10. Frost, S. D., Wrin, T., Smith, D. M., Kosakovsky Pond, S. L., Liu, Y., Paxinos, E., Chappey, C., Galovich, J., Beauchaine, J. & other authors ( 2005; ). Neutralizing antibody responses drive the evolution of human immunodeficiency virus type 1 envelope during recent HIV infection. Proc Natl Acad Sci U S A 102, 18514–18519.[CrossRef]
    [Google Scholar]
  11. Gartner, S., Markovits, P., Markovitz, D. M., Kaplan, M. H., Gallo, R. C. & Popovic, M. ( 1986; ). The role of mononuclear phagocytes in HTLV-III/LAV infection. Science 233, 215–219.[CrossRef]
    [Google Scholar]
  12. Gorny, M. K., Revesz, K., Williams, C., Volsky, B., Louder, M. K., Anyangwe, C. A., Krachmarov, C., Kayman, S. C., Pinter, A. & other authors ( 2004; ). The V3 loop is accessible on the surface of most human immunodeficiency virus type 1 primary isolates and serves as a neutralization epitope. J Virol 78, 2394–2404.[CrossRef]
    [Google Scholar]
  13. Guex, N., Diemand, A. & Peitsch, M. C. ( 1999; ). Protein modelling for all. Trends Biochem Sci 24, 364–367.[CrossRef]
    [Google Scholar]
  14. Hope, T. J., Huang, X. J., McDonald, D. & Parslow, T. G. ( 1990; ). Steroid-receptor fusion of the human immunodeficiency virus type 1 Rev transactivator: mapping cryptic functions of the arginine-rich motif. Proc Natl Acad Sci U S A 87, 7787–7791.[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. Johnson, W. E. & Desrosiers, R. C. ( 2002; ). Viral persistence: HIV's strategies of immune system evasion. Annu Rev Med 53, 499–518.[CrossRef]
    [Google Scholar]
  17. Joos, B., Trkola, A., Kuster, H., Aceto, L., Fischer, M., Stiegler, G., Armbruster, C., Vcelar, B., Katinger, H. & Gunthard, H. F. ( 2006; ). Long-term multiple-dose pharmacokinetics of human monoclonal antibodies (MAbs) against human immunodeficiency virus type 1 envelope gp120 (MAb 2G12) and gp41 (MAbs 4E10 and 2F5). Antimicrob Agents Chemother 50, 1773–1779.[CrossRef]
    [Google Scholar]
  18. Krachmarov, C., Pinter, A., Honnen, W. J., Gorny, M. K., Nyambi, P. N., Zolla-Pazner, S. & Kayman, S. C. ( 2005; ). Antibodies that are cross-reactive for human immunodeficiency virus type 1 clade A and clade B V3 domains are common in patient sera from Cameroon, but their neutralization activity is usually restricted by epitope masking. J Virol 79, 780–790.[CrossRef]
    [Google Scholar]
  19. Kuhmann, S. E., Pugach, P., Kunstman, K. J., Taylor, J., Stanfield, R. L., Snyder, A., Strizki, J. M., Riley, J., Baroudy, B. M. & other authors ( 2004; ). Genetic and phenotypic analyses of human immunodeficiency virus type 1 escape from a small-molecule CCR5 inhibitor. J Virol 78, 2790–2807.[CrossRef]
    [Google Scholar]
  20. Kwong, P. D., Doyle, M. L., Casper, D. J., Cicala, C., Leavitt, S. A., Majeed, S., Steenbeke, T. D., Venturi, M., Chaiken, I. & other authors ( 2002; ). HIV-1 evades antibody-mediated neutralization through conformational masking of receptor-binding sites. Nature 420, 678–682.[CrossRef]
    [Google Scholar]
  21. Li, M., Gao, F., Mascola, J. R., Stamatatos, L., Polonis, V. R., Koutsoukos, M., Voss, G., Goepfert, P., Gilbert, P. & other authors ( 2005; ). Human immunodeficiency virus type 1 env clones from acute and early subtype B infections for standardized assessments of vaccine-elicited neutralizing antibodies. J Virol 79, 10108–10125.[CrossRef]
    [Google Scholar]
  22. Mahalanabis, M., Jayaraman, P., Miura, T., Pereyra, F., Chester, E. M., Richardson, B., Walker, B. & Haigwood, N. L. ( 2009; ). Continuous viral escape and selection by autologous neutralizing antibodies in drug-naive human immunodeficiency virus controllers. J Virol 83, 662–672.[CrossRef]
    [Google Scholar]
  23. Manrique, A., Rusert, P., Joos, B., Fischer, M., Kuster, H., Leemann, C., Niederost, B., Weber, R., Stiegler, G. & other authors ( 2007; ). In vivo and in vitro escape from neutralizing antibodies 2G12, 2F5, and 4E10. J Virol 81, 8793–8808.[CrossRef]
    [Google Scholar]
  24. Marozsan, A. J., Kuhmann, S. E., Morgan, T., Herrera, C., Rivera-Troche, E., Xu, S., Baroudy, B. M., Strizki, J. & Moore, J. P. ( 2005; ). Generation and properties of a human immunodeficiency virus type 1 isolate resistant to the small molecule CCR5 inhibitor, SCH-417690 (SCH-D). Virology 338, 182–199.[CrossRef]
    [Google Scholar]
  25. Masuda, T., Matsushita, S., Kuroda, M. J., Kannagi, M., Takatsuki, K. & Harada, S. ( 1990; ). Generation of neutralization-resistant HIV-1 in vitro due to amino acid interchanges of third hypervariable env region. J Immunol 145, 3240–3246.
    [Google Scholar]
  26. McCaffrey, R. A., Saunders, C., Hensel, M. & Stamatatos, L. ( 2004; ). N-linked glycosylation of the V3 loop and the immunologically silent face of gp120 protects human immunodeficiency virus type 1 SF162 from neutralization by anti-gp120 and anti-gp41 antibodies. J Virol 78, 3279–3295.[CrossRef]
    [Google Scholar]
  27. Montefiori, D. C., Hill, T. S., Vo, H. T., Walker, B. D. & Rosenberg, E. S. ( 2001; ). Neutralizing antibodies associated with viremia control in a subset of individuals after treatment of acute human immunodeficiency virus type 1 infection. J Virol 75, 10200–10207.[CrossRef]
    [Google Scholar]
  28. Moore, J. P., Cao, Y., Qing, L., Sattentau, Q. J., Pyati, J., Koduri, R., Robinson, J., Barbas, C. F., III, Burton, D. R. & Ho, D. D. ( 1995; ). Primary isolates of human immunodeficiency virus type 1 are relatively resistant to neutralization by monoclonal antibodies to gp120, and their neutralization is not predicted by studies with monomeric gp120. J Virol 69, 101–109.
    [Google Scholar]
  29. Nabatov, A. A., Pollakis, G., Linnemann, T., Kliphius, A., Chalaby, M. I. & Paxton, W. A. ( 2004; ). Intrapatient alterations in the human immunodeficiency virus type 1 gp120 V1V2 and V3 regions differentially modulate coreceptor usage, virus inhibition by CC/CXC chemokines, soluble CD4, and the b12 and 2G12 monoclonal antibodies. J Virol 78, 524–530.[CrossRef]
    [Google Scholar]
  30. Ogert, R. A., Wojcik, L., Buontempo, C., Ba, L., Buontempo, P., Ralston, R., Strizki, J. & Howe, J. A. ( 2008; ). Mapping resistance to the CCR5 co-receptor antagonist vicriviroc using heterologous chimeric HIV-1 envelope genes reveals key determinants in the C2–V5 domain of gp120. Virology 373, 387–399.[CrossRef]
    [Google Scholar]
  31. Park, E. J., Vujcic, L. K., Anand, R., Theodore, T. S. & Quinnan, G. V., Jr ( 1998; ). Mutations in both gp120 and gp41 are responsible for the broad neutralization resistance of variant human immunodeficiency virus type 1 MN to antibodies directed at V3 and non-V3 epitopes. J Virol 72, 7099–7107.
    [Google Scholar]
  32. Pinter, A., Honnen, W. J., He, Y., Gorny, M. K., Zolla-Pazner, S. & Kayman, S. C. ( 2004; ). The V1/V2 domain of gp120 is a global regulator of the sensitivity of primary human immunodeficiency virus type 1 isolates to neutralization by antibodies commonly induced upon infection. J Virol 78, 5205–5215.[CrossRef]
    [Google Scholar]
  33. Pinter, A., Honnen, W. J., D'Agostino, P., Gorny, M. K., Zolla-Pazner, S. & Kayman, S. C. ( 2005; ). The C108g epitope in the V2 domain of gp120 functions as a potent neutralization target when introduced into envelope proteins derived from human immunodeficiency virus type 1 primary isolates. J Virol 79, 6909–6917.[CrossRef]
    [Google Scholar]
  34. Platt, E. J., Wehrly, K., Kuhmann, S. E., Chesebro, B. & Kabat, D. ( 1998; ). Effects of CCR5 and CD4 cell surface concentrations on infections by macrophagetropic isolates of human immunodeficiency virus type 1. J Virol 72, 2855–2864.
    [Google Scholar]
  35. Pugach, P., Kuhmann, S. E., Taylor, J., Marozsan, A. J., Snyder, A., Ketas, T., Wolinsky, S. M., Korber, B. T. & Moore, J. P. ( 2004; ). The prolonged culture of human immunodeficiency virus type 1 in primary lymphocytes increases its sensitivity to neutralization by soluble CD4. Virology 321, 8–22.[CrossRef]
    [Google Scholar]
  36. 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]
  37. Sagar, M., Wu, X., Lee, S. & Overbaugh, J. ( 2006; ). Human immunodeficiency virus type 1 V1–V2 envelope loop sequences expand and add glycosylation sites over the course of infection, and these modifications affect antibody neutralization sensitivity. J Virol 80, 9586–9598.[CrossRef]
    [Google Scholar]
  38. Saunders, C. J., McCaffrey, R. A., Zharkikh, I., Kraft, Z., Malenbaum, S. E., Burke, B., Cheng-Mayer, C. & Stamatatos, L. ( 2005; ). The V1, V2, and V3 regions of the human immunodeficiency virus type 1 envelope differentially affect the viral phenotype in an isolate-dependent manner. J Virol 79, 9069–9080.[CrossRef]
    [Google Scholar]
  39. Shibata, J., Yoshimura, K., Honda, A., Koito, A., Murakami, T. & Matsushita, S. ( 2007; ). Impact of V2 mutations on escape from a potent neutralizing anti-V3 monoclonal antibody during in vitro selection of a primary human immunodeficiency virus type 1 isolate. J Virol 81, 3757–3768.[CrossRef]
    [Google Scholar]
  40. Sullivan, N., Thali, M., Furman, C., Ho, D. D. & Sodroski, J. ( 1993; ). Effect of amino acid changes in the V1/V2 region of the human immunodeficiency virus type 1 gp120 glycoprotein on subunit association, syncytium formation, and recognition by a neutralizing antibody. J Virol 67, 3674–3679.
    [Google Scholar]
  41. Trkola, A., Kuster, H., Rusert, P., Joos, B., Fischer, M., Leemann, C., Manrique, A., Huber, M., Rehr, M. & other authors ( 2005; ). Delay of HIV-1 rebound after cessation of antiretroviral therapy through passive transfer of human neutralizing antibodies. Nat Med 11, 615–622.[CrossRef]
    [Google Scholar]
  42. Trkola, A., Kuster, H., Rusert, P., von Wyl, V., Leemann, C., Weber, R., Stiegler, G., Katinger, H., Joos, B. & Gunthard, H. F. ( 2008; ). In vivo efficacy of human immunodeficiency virus neutralizing antibodies: estimates for protective titers. J Virol 82, 1591–1599.[CrossRef]
    [Google Scholar]
  43. Wang, F. X., Kimura, T., Nishihara, K., Yoshimura, K., Koito, A. & Matsushita, S. ( 2002; ). Emergence of autologous neutralization-resistant variants from preexisting human immunodeficiency virus (HIV) quasi species during virus rebound in HIV type 1-infected patients undergoing highly active antiretroviral therapy. J Infect Dis 185, 608–617.[CrossRef]
    [Google Scholar]
  44. Wei, X., Decker, J. M., Liu, H., Zhang, Z., Arani, R. B., Kilby, J. M., Saag, M. S., Wu, X., Shaw, G. M. & Kappes, J. C. ( 2002; ). Emergence of resistant human immunodeficiency virus type 1 in patients receiving fusion inhibitor (T-20) monotherapy. Antimicrob Agents Chemother 46, 1896–1905.[CrossRef]
    [Google Scholar]
  45. Wei, X., Decker, J. M., Wang, S., Hui, H., Kappes, J. C., Wu, X., Salazar-Gonzalez, J. F., Salazar, M. G., Kilby, J. M. & other authors ( 2003; ). Antibody neutralization and escape by HIV-1. Nature 422, 307–312.[CrossRef]
    [Google Scholar]
  46. Westby, M., Smith-Burchnell, C., Mori, J., Lewis, M., Mosley, M., Stockdale, M., Dorr, P., Ciaramella, G. & Perros, M. ( 2007; ). Reduced maximal inhibition in phenotypic susceptibility assays indicates that viral strains resistant to the CCR5 antagonist maraviroc utilize inhibitor-bound receptor for entry. J Virol 81, 2359–2371.[CrossRef]
    [Google Scholar]
  47. Yoshimura, K., Shibata, J., Kimura, T., Honda, A., Maeda, Y., Koito, A., Murakami, T., Mitsuya, H. & Matsushita, S. ( 2006; ). Resistance profile of a neutralizing anti-HIV monoclonal antibody, KD-247, that shows favourable synergism with anti-CCR5 inhibitors. AIDS 20, 2065–2073.[CrossRef]
    [Google Scholar]
  48. Yusa, K., Maeda, Y., Fujioka, A., Monde, K. & Harada, S. ( 2005; ). Isolation of TAK-779-resistant HIV-1 from an R5 HIV-1 GP120 V3 loop library. J Biol Chem 280, 30083–30090.[CrossRef]
    [Google Scholar]
  49. Zhu, X., Borchers, C., Bienstock, R. J. & Tomer, K. B. ( 2000; ). Mass spectrometric characterization of the glycosylation pattern of HIV-gp120 expressed in CHO cells. Biochemistry 39, 11194–11204.[CrossRef]
    [Google Scholar]
  50. Zolla-Pazner, S. ( 2004; ). Identifying epitopes of HIV-1 that induce protective antibodies. Nat Rev Immunol 4, 199–210.[CrossRef]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.017426-0
Loading
/content/journal/jgv/10.1099/vir.0.017426-0
Loading

Data & Media loading...

Supplements

vol. , part 5, pp. 1335 - 1345

Simulation of the V3-loop structures [PDF](48 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