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Volume 91, Issue 12

C-C chemokine receptor type 5 (CCR5) utilization of transmitted and early founder human immunodeficiency virus type 1 envelopes and sensitivity to small-molecule CCR5 inhibitors Free

Abstract

The envelope glycoprotein (Env) of human immunodeficiency virus is key to viral entry of susceptible target cells and is therefore a major target for the design of vaccines and antiviral drugs. C-C chemokine receptor type 5 (CCR5)-using (R5) Env is the predominant phenotype associated with early transmission and acute infection. This study investigated the mechanism of CCR5 use and the sensitivity to CCR5 inhibitors of a panel of transmitted or early founder (T/F) Envs. The data showed that the majority of T/F Envs used CCR5 and that many also used CCR3, although less efficiently. Despite a similar ability to use wild-type CCR5, individual Envs differed significantly in their sensitivity to the CCR5 inhibitors maraviroc, CMPD-167 and SCH-412147. Inhibitor mapping experiments demonstrated that maraviroc, CMPD-167 and SCH-412147 interfered with the binding of CCR5 mAb to the C-terminal half of the second extracellular loop 2 of CCR5. Interestingly, Envs resistant to maraviroc, CMPD167 and SCH-412147 remained sensitive to TAK-779. Further studies indicated that the sensitivity of Envs to CCR5 inhibitors correlated with the molecular anatomy of CCR5 use, revealing that the inhibitor-sensitive Envs barely used the CCR5 N terminus, whereas resistant Envs showed a marked increase in its use. Taken together, these findings demonstrate that T/F R5 Envs are heterogeneous with respect to the mechanisms of CCR5 utilization. These data may have implications for therapeutic and prophylactic use of CCR5-based antiretrovirals.

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2010-12-01
2024-04-19
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References

  1. Aasa-Chapman, M. M., Seymour, C. R., Williams, I. & McKnight, A.(2006). Novel envelope determinants for CCR3 use by human immunodeficiency virus. J Virol 80, 10884–10889.[CrossRef] [Google Scholar]
  2. 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]
  3. Baba, M., Nishimura, O., Kanzaki, N., Okamoto, M., Sawada, H., Iizawa, Y., Shiraishi, M., Aramaki, Y., Okonogi, K. & other authors(1999). A small-molecule, nonpeptide CCR5 antagonist with highly potent and selective anti-HIV-1 activity. Proc Natl Acad Sci U S A 96, 5698–5703.[CrossRef] [Google Scholar]
  4. 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]
  5. Briz, V., Poveda, E. & Soriano, V.(2006). HIV entry inhibitors: mechanisms of action and resistance pathways. J Antimicrob Chemother 57, 619–627.[CrossRef] [Google Scholar]
  6. Dorr, P., Westby, M., Dobbs, S., Griffin, P., Irvine, B., Macartney, M., Mori, J., Rickett, G., Smith-Burchnell, C. & other authors(2005). Maraviroc (UK-427,857), a potent, orally bioavailable, and selective small-molecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-human immunodeficiency virus type 1 activity. Antimicrob Agents Chemother 49, 4721–4732.[CrossRef] [Google Scholar]
  7. Dragic, T., Trkola, A., Thompson, D. A., Cormier, E. G., Kajumo, F. A., Maxwell, E., Lin, S. W., Ying, W., Smith, S. O. & other authors(2000). A binding pocket for a small molecule inhibitor of HIV-1 entry within the transmembrane helices of CCR5. Proc Natl Acad Sci U S A 97, 5639–5644.[CrossRef] [Google Scholar]
  8. Gao, P., Zhou, X. Y., Yashiro-Ohtani, Y., Yang, Y. F., Sugimoto, N., Ono, S., Nakanishi, T., Obika, S., Imanishi, T. & other authors(2003). The unique target specificity of a nonpeptide chemokine receptor antagonist: selective blockade of two Th1 chemokine receptors CCR5 and CXCR3. J Leukoc Biol 73, 273–280.[CrossRef] [Google Scholar]
  9. Gulick, R. M., Su, Z., Flexner, C., Hughes, M. D., Skolnik, P. R., Wilkin, T. J., Gross, R., Krambrink, A., Coakley, E. & other authors(2007). Phase 2 study of the safety and efficacy of vicriviroc, a CCR5 inhibitor, in HIV-1-infected, treatment-experienced patients: AIDS clinical trials group 5211. J Infect Dis 196, 304–312.[CrossRef] [Google Scholar]
  10. Gulick, R. M., Lalezari, J., Goodrich, J., Clumeck, N., DeJesus, E., Horban, A., Nadler, J., Clotet, B., Karlsson, A. & other authors(2008). Maraviroc for previously treated patients with R5 HIV-1 infection. N Engl J Med 359, 1429–1441.[CrossRef] [Google Scholar]
  11. Hu, Q., Barry, A. P., Wang, Z., Connolly, S. M., Peiper, S. C. & Greenberg, M. L.(2000a). Evolution of the human immunodeficiency virus type 1 envelope during infection reveals molecular corollaries of specificity for coreceptor utilization and AIDS pathogenesis. J Virol 74, 11858–11872.[CrossRef] [Google Scholar]
  12. Hu, Q., Trent, J. O., Tomaras, G. D., Wang, Z., Murray, J. L., Conolly, S. M., Navenot, J. M., Barry, A. P., Greenberg, M. L. & other authors(2000b). Identification of Env determinants in V3 that influence the molecular anatomy of CCR5 utilization. J Mol Biol 302, 359–375.[CrossRef] [Google Scholar]
  13. Hu, Q., Frank, I., Williams, V., Santos, J. J., Watts, P., Griffin, G. E., Moore, J. P., Pope, M. & Shattock, R. J.(2004). Blockade of attachment and fusion receptors inhibits HIV-1 infection of human cervical tissue. J Exp Med 199, 1065–1075.[CrossRef] [Google Scholar]
  14. Hu, Q., Napier, K. B., Trent, J. O., Wang, Z., Taylor, S., Griffin, G. E., Peiper, S. C. & Shattock, R. J.(2005). Restricted variable residues in the C-terminal segment of HIV-1 V3 loop regulate the molecular anatomy of CCR5 utilization. J Mol Biol 350, 699–712.[CrossRef] [Google Scholar]
  15. 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]
  16. Ketas, T. J., Kuhmann, S. E., Palmer, A., Zurita, J., He, W., Ahuja, S. K., Klasse, P. J. & Moore, J. P.(2007). Cell surface expression of CCR5 and other host factors influence the inhibition of HIV-1 infection of human lymphocytes by CCR5 ligands. Virology 364, 281–290.[CrossRef] [Google Scholar]
  17. Klasse, P. J., Shattock, R. & Moore, J. P.(2008). Antiretroviral drug-based microbicides to prevent HIV-1 sexual transmission. Annu Rev Med 59, 455–471.[CrossRef] [Google Scholar]
  18. Kondru, R., Zhang, J., Ji, C., Mirzadegan, T., Rotstein, D., Sankuratri, S. & Dioszegi, M.(2008). Molecular interactions of CCR5 with major classes of small-molecule anti-HIV CCR5 antagonists. Mol Pharmacol 73, 789–800. [Google Scholar]
  19. Kuhmann, S. E. & Hartley, O.(2008). Targeting chemokine receptors in HIV: a status report. Annu Rev Pharmacol Toxicol 48, 425–461.[CrossRef] [Google Scholar]
  20. Lee, B., Sharron, M., Blanpain, C., Doranz, B. J., Vakili, J., Setoh, P., Berg, E., Liu, G., Guy, H. R. & other authors(1999). Epitope mapping of CCR5 reveals multiple conformational states and distinct but overlapping structures involved in chemokine and coreceptor function. J Biol Chem 274, 9617–9626.[CrossRef] [Google Scholar]
  21. Maeda, K., Das, D., Ogata-Aoki, H., Nakata, H., Miyakawa, T., Tojo, Y., Norman, R., Takaoka, Y., Ding, J. & other authors(2006). Structural and molecular interactions of CCR5 inhibitors with CCR5. J Biol Chem 281, 12688–12698.[CrossRef] [Google Scholar]
  22. McMichael, A. J., Borrow, P., Tomaras, G. D., Goonetilleke, N. & Haynes, B. F.(2010). The immune response during acute HIV-1 infection: clues for vaccine development. Nat Rev Immunol 10, 11–23.[CrossRef] [Google Scholar]
  23. Nedellec, R., Coetzer, M., Shimizu, N., Hoshino, H., Polonis, V. R., Morris, L., Martensson, U. E., Binley, J., Overbaugh, J. & other authors(2009). Virus entry via the alternative coreceptors CCR3 and FPRL1 differs by human immunodeficiency virus type 1 subtype. J Virol 83, 8353–8363.[CrossRef] [Google Scholar]
  24. 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]
  25. Ogert, R. A., Ba, L., Hou, Y., Buontempo, C., Qiu, P., Duca, J., Murgolo, N., Buontempo, P., Ralston, R. & other authors(2009). Structure–function analysis of human immunodeficiency virus type 1 gp120 amino acid mutations associated with resistance to the CCR5 coreceptor antagonist vicriviroc. J Virol 83, 12151–12163.[CrossRef] [Google Scholar]
  26. Ogert, R. A., Hou, Y., Ba, L., Wojcik, L., Qiu, P., Murgolo, N., Duca, J., Dunkle, L. M., Ralston, R. & other authors(2010). Clinical resistance to vicriviroc through adaptive V3 loop mutations in HIV-1 subtype D gp120 that alter interactions with the N-terminus and ECL2 of CCR5. Virology 400, 145–155.[CrossRef] [Google Scholar]
  27. Reeves, J. D., Gallo, S. A., Ahmad, N., Miamidian, J. L., Harvey, P. E., Sharron, M., Pohlmann, S., Sfakianos, J. N., Derdeyn, C. A. & other authors(2002). Sensitivity of HIV-1 to entry inhibitors correlates with envelope/coreceptor affinity, receptor density, and fusion kinetics. Proc Natl Acad Sci U S A 99, 16249–16254.[CrossRef] [Google Scholar]
  28. Schürmann, D., Fätkenheuer, G., Reynes, J., Michelet, C., Raffi, F., van Lier, J., Caceres, M., Keung, A., Sansone-Parsons, A. & other authors(2007). Antiviral activity, pharmacokinetics and safety of vicriviroc, an oral CCR5 antagonist, during 14-day monotherapy in HIV-infected adults. AIDS 21, 1293–1299.[CrossRef] [Google Scholar]
  29. Seibert, C., Ying, W., Gavrilov, S., Tsamis, F., Kuhmann, S. E., Palani, A., Tagat, J. R., Clader, J. W., McCombie, S. W. & other authors(2006). Interaction of small molecule inhibitors of HIV-1 entry with CCR5. Virology 349, 41–54.[CrossRef] [Google Scholar]
  30. Shattock, R. J. & Moore, J. P.(2003). Inhibiting sexual transmission of HIV-1 infection. Nat Rev Microbiol 1, 25–34.[CrossRef] [Google Scholar]
  31. Tsamis, F., Gavrilov, S., Kajumo, F., Seibert, C., Kuhmann, S., Ketas, T., Trkola, A., Palani, A., Clader, J. W. & other authors(2003). Analysis of the mechanism by which the small-molecule CCR5 antagonists SCH-351125 and SCH-350581 inhibit human immunodeficiency virus type 1 entry. J Virol 77, 5201–5208.[CrossRef] [Google Scholar]
  32. Tsibris, A. M., Sagar, M., Gulick, R. M., Su, Z., Hughes, M., Greaves, W., Subramanian, M., Flexner, C., Giguel, F. & other authors(2008). In vivo emergence of vicriviroc resistance in a human immunodeficiency virus type 1 subtype C-infected subject. J Virol 82, 8210–8214.[CrossRef] [Google Scholar]
  33. Veazey, R. S., Klasse, P. J., Schader, S. M., Hu, Q., Ketas, T. J., Lu, M., Marx, P. A., Dufour, J., Colonno, R. J. & other authors(2005). Protection of macaques from vaginal SHIV challenge by vaginally delivered inhibitors of virus–cell fusion. Nature 438, 99–102.[CrossRef] [Google Scholar]
  34. 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]
  35. Wu, L., LaRosa, G., Kassam, N., Gordon, C. J., Heath, H., Ruffing, N., Chen, H., Humblias, J., Samson, M. & other authors(1997). Interaction of chemokine receptor CCR5 with its ligands: multiple domains for HIV-1 gp120 binding and a single domain for chemokine binding. J Exp Med 186, 1373–1381.[CrossRef] [Google Scholar]
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C-C chemokine receptor type 5 (CCR5) utilization of transmitted and early founder human immunodeficiency virus type 1 envelopes and sensitivity to small-molecule CCR5 inhibitors
J. Gen. Virol. 91, 2965 (2010); https://doi.org/10.1099/vir.0.025270-0
/content/journal/jgv/10.1099/vir.0.025270-0
/content/journal/jgv/10.1099/vir.0.025270-0
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