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. 1996 Dec;70(12):9055–9059. doi: 10.1128/jvi.70.12.9055-9059.1996

Mapping of independent V3 envelope determinants of human immunodeficiency virus type 1 macrophage tropism and syncytium formation in lymphocytes.

B Chesebro 1, K Wehrly 1, J Nishio 1, S Perryman 1
PMCID: PMC191011  PMID: 8971043

Abstract

The V3 region of the human immunodeficiency virus type 1 (HIV-1) envelope protein is known to have a major influence on macrophage tropism as well as the ability to cause syncytium formation or fusion in CD4-positive lymphocyte cultures. Using infectious molecular HIV-1 clones, a series of mutant clones was created which allowed detailed mapping of V3 amino acid positions involved in these properties. In these experiments the non-syncytium-inducing phenotype in T cells did not always correlate with macrophage tropism. Macrophage tropism appeared to depend on the presence of certain combinations of amino acids at five specific positions within and just outside of the V3 loop itself, whereas syncytium formation in lymphocytes was influenced by substitution of particular residues at two to four positions within V3. In most cases, different V3 amino acid positions were found to independently influence macrophage tropism and syncytium formation in T cells and position 13 was the only V3 location which appeared to simultaneously influence both macrophage tropism and syncytium formation in lymphocytes.

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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. Asjö B., Morfeldt-Månson L., Albert J., Biberfeld G., Karlsson A., Lidman K., Fenyö E. M. Replicative capacity of human immunodeficiency virus from patients with varying severity of HIV infection. Lancet. 1986 Sep 20;2(8508):660–662. [PubMed] [Google Scholar]
  3. Balliet J. W., Kolson D. L., Eiger G., Kim F. M., McGann K. A., Srinivasan A., Collman R. Distinct effects in primary macrophages and lymphocytes of the human immunodeficiency virus type 1 accessory genes vpr, vpu, and nef: mutational analysis of a primary HIV-1 isolate. Virology. 1994 May 1;200(2):623–631. doi: 10.1006/viro.1994.1225. [DOI] [PubMed] [Google Scholar]
  4. Balotta C., Lusso P., Crowley R., Gallo R. C., Franchini G. Antisense phosphorothioate oligodeoxynucleotides targeted to the vpr gene inhibit human immunodeficiency virus type 1 replication in primary human macrophages. J Virol. 1993 Jul;67(7):4409–4414. doi: 10.1128/jvi.67.7.4409-4414.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Banapour B., Marthas M. L., Ramos R. A., Lohman B. L., Unger R. E., Gardner M. B., Pedersen N. C., Luciw P. A. Identification of viral determinants of macrophage tropism for simian immunodeficiency virus SIVmac. J Virol. 1991 Nov;65(11):5798–5805. doi: 10.1128/jvi.65.11.5798-5805.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cheng-Mayer C., Seto D., Tateno M., Levy J. A. Biologic features of HIV-1 that correlate with virulence in the host. Science. 1988 Apr 1;240(4848):80–82. doi: 10.1126/science.2832945. [DOI] [PubMed] [Google Scholar]
  7. Chesebro B., Wehrly K., Metcalf J., Griffin D. E. Use of a new CD4-positive HeLa cell clone for direct quantitation of infectious human immunodeficiency virus from blood cells of AIDS patients. J Infect Dis. 1991 Jan;163(1):64–70. doi: 10.1093/infdis/163.1.64. [DOI] [PubMed] [Google Scholar]
  8. Chesebro B., Wehrly K., Nishio J., Evans L. Leukemia induction by a new strain of Friend mink cell focus-inducing virus: synergistic effect of Friend ecotropic murine leukemia virus. J Virol. 1984 Jul;51(1):63–70. doi: 10.1128/jvi.51.1.63-70.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Chesebro B., Wehrly K., Nishio J., Perryman S. Macrophage-tropic human immunodeficiency virus isolates from different patients exhibit unusual V3 envelope sequence homogeneity in comparison with T-cell-tropic isolates: definition of critical amino acids involved in cell tropism. J Virol. 1992 Nov;66(11):6547–6554. doi: 10.1128/jvi.66.11.6547-6554.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Choe H., Farzan M., Sun Y., Sullivan N., Rollins B., Ponath P. D., Wu L., Mackay C. R., LaRosa G., Newman W. The beta-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates. Cell. 1996 Jun 28;85(7):1135–1148. doi: 10.1016/s0092-8674(00)81313-6. [DOI] [PubMed] [Google Scholar]
  11. Cloyd M. W., Hartley J. W., Rowe W. P. Genetic study of lymphoma induction by AKR mink cell focus-inducing virus in AKR x NFS crosses. J Exp Med. 1981 Aug 1;154(2):450–457. doi: 10.1084/jem.154.2.450. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Coffin J. M. HIV population dynamics in vivo: implications for genetic variation, pathogenesis, and therapy. Science. 1995 Jan 27;267(5197):483–489. doi: 10.1126/science.7824947. [DOI] [PubMed] [Google Scholar]
  13. Collman R., Balliet J. W., Gregory S. A., Friedman H., Kolson D. L., Nathanson N., Srinivasan A. An infectious molecular clone of an unusual macrophage-tropic and highly cytopathic strain of human immunodeficiency virus type 1. J Virol. 1992 Dec;66(12):7517–7521. doi: 10.1128/jvi.66.12.7517-7521.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. De Jong J. J., De Ronde A., Keulen W., Tersmette M., Goudsmit J. 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. 1992 Nov;66(11):6777–6780. doi: 10.1128/jvi.66.11.6777-6780.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Deng H., Liu R., Ellmeier W., Choe S., Unutmaz D., Burkhart M., Di Marzio P., Marmon S., Sutton R. E., Hill C. M. Identification of a major co-receptor for primary isolates of HIV-1. Nature. 1996 Jun 20;381(6584):661–666. doi: 10.1038/381661a0. [DOI] [PubMed] [Google Scholar]
  16. Doranz B. J., Rucker J., Yi Y., Smyth R. J., Samson M., Peiper S. C., Parmentier M., Collman R. G., Doms R. W. A dual-tropic primary HIV-1 isolate that uses fusin and the beta-chemokine receptors CKR-5, CKR-3, and CKR-2b as fusion cofactors. Cell. 1996 Jun 28;85(7):1149–1158. doi: 10.1016/s0092-8674(00)81314-8. [DOI] [PubMed] [Google Scholar]
  17. Dragic T., Litwin V., Allaway G. P., Martin S. R., Huang Y., Nagashima K. A., Cayanan C., Maddon P. J., Koup R. A., Moore J. P. HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5. Nature. 1996 Jun 20;381(6584):667–673. doi: 10.1038/381667a0. [DOI] [PubMed] [Google Scholar]
  18. Feng Y., Broder C. C., Kennedy P. E., Berger E. A. HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science. 1996 May 10;272(5263):872–877. doi: 10.1126/science.272.5263.872. [DOI] [PubMed] [Google Scholar]
  19. Fenyö E. M., Morfeldt-Månson L., Chiodi F., Lind B., von Gegerfelt A., Albert J., Olausson E., Asjö B. Distinct replicative and cytopathic characteristics of human immunodeficiency virus isolates. J Virol. 1988 Nov;62(11):4414–4419. doi: 10.1128/jvi.62.11.4414-4419.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Fouchier R. A., Brouwer M., Kootstra N. A., Huisman H. G., Schuitemaker H. HIV-1 macrophage tropism is determined at multiple levels of the viral replication cycle. J Clin Invest. 1994 Nov;94(5):1806–1814. doi: 10.1172/JCI117529. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Fouchier R. A., Groenink M., Kootstra N. A., Tersmette M., Huisman H. G., Miedema F., Schuitemaker H. Phenotype-associated sequence variation in the third variable domain of the human immunodeficiency virus type 1 gp120 molecule. J Virol. 1992 May;66(5):3183–3187. doi: 10.1128/jvi.66.5.3183-3187.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Groenink M., Fouchier R. A., Broersen S., Baker C. H., Koot M., van't Wout A. B., Huisman H. G., Miedema F., Tersmette M., Schuitemaker H. Relation of phenotype evolution of HIV-1 to envelope V2 configuration. Science. 1993 Jun 4;260(5113):1513–1516. doi: 10.1126/science.8502996. [DOI] [PubMed] [Google Scholar]
  23. Holm-Hansen C., Grothues D., Rustad S., Røsok B., Pascu F. R., Asjö B. Characterization of HIV type 1 from Romanian children: lack of correlation between V3 loop amino acid sequence and syncytium formation in MT-2 cells. AIDS Res Hum Retroviruses. 1995 May;11(5):597–603. doi: 10.1089/aid.1995.11.597. [DOI] [PubMed] [Google Scholar]
  24. Hwang S. S., Boyle T. J., Lyerly H. K., Cullen B. R. Identification of the envelope V3 loop as the primary determinant of cell tropism in HIV-1. Science. 1991 Jul 5;253(5015):71–74. doi: 10.1126/science.1905842. [DOI] [PubMed] [Google Scholar]
  25. Karlsson A., Parsmyr K., Sandström E., Fenyö E. M., Albert J. MT-2 cell tropism as prognostic marker for disease progression in human immunodeficiency virus type 1 infection. J Clin Microbiol. 1994 Feb;32(2):364–370. doi: 10.1128/jcm.32.2.364-370.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Kim F. M., Kolson D. L., Balliet J. W., Srinivasan A., Collman R. G. V3-independent determinants of macrophage tropism in a primary human immunodeficiency virus type 1 isolate. J Virol. 1995 Mar;69(3):1755–1761. doi: 10.1128/jvi.69.3.1755-1761.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Koito A., Harrowe G., Levy J. A., Cheng-Mayer C. Functional role of the V1/V2 region of human immunodeficiency virus type 1 envelope glycoprotein gp120 in infection of primary macrophages and soluble CD4 neutralization. J Virol. 1994 Apr;68(4):2253–2259. doi: 10.1128/jvi.68.4.2253-2259.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Koot M., Vos A. H., Keet R. P., de Goede R. E., Dercksen M. W., Terpstra F. G., Coutinho R. A., Miedema F., Tersmette M. HIV-1 biological phenotype in long-term infected individuals evaluated with an MT-2 cocultivation assay. AIDS. 1992 Jan;6(1):49–54. doi: 10.1097/00002030-199201000-00006. [DOI] [PubMed] [Google Scholar]
  29. Koyanagi Y., Miles S., Mitsuyasu R. T., Merrill J. E., Vinters H. V., Chen I. S. Dual infection of the central nervous system by AIDS viruses with distinct cellular tropisms. Science. 1987 May 15;236(4803):819–822. doi: 10.1126/science.3646751. [DOI] [PubMed] [Google Scholar]
  30. Malykh A., Reitz M. S., Jr, Louie A., Hall L., Lori F. Multiple determinants for growth of human immunodeficiency virus type 1 in monocyte-macrophages. Virology. 1995 Jan 10;206(1):646–650. doi: 10.1016/s0042-6822(95)80082-4. [DOI] [PubMed] [Google Scholar]
  31. Mammano F., Salvatori F., Ometto L., Panozzo M., Chieco-Bianchi L., De Rossi A. Relationship between the V3 loop and the phenotypes of human immunodeficiency virus type 1 (HIV-1) isolates from children perinatally infected with HIV-1. J Virol. 1995 Jan;69(1):82–92. doi: 10.1128/jvi.69.1.82-92.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. McNearney T., Hornickova Z., Markham R., Birdwell A., Arens M., Saah A., Ratner L. Relationship of human immunodeficiency virus type 1 sequence heterogeneity to stage of disease. Proc Natl Acad Sci U S A. 1992 Nov 1;89(21):10247–10251. doi: 10.1073/pnas.89.21.10247. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Mori K., Ringler D. J., Kodama T., Desrosiers R. C. Complex determinants of macrophage tropism in env of simian immunodeficiency virus. J Virol. 1992 Apr;66(4):2067–2075. doi: 10.1128/jvi.66.4.2067-2075.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. O'Brien W. A., Koyanagi Y., Namazie A., Zhao J. Q., Diagne A., Idler K., Zack J. A., Chen I. S. HIV-1 tropism for mononuclear phagocytes can be determined by regions of gp120 outside the CD4-binding domain. Nature. 1990 Nov 1;348(6296):69–73. doi: 10.1038/348069a0. [DOI] [PubMed] [Google Scholar]
  35. Power C., McArthur J. C., Johnson R. T., Griffin D. E., Glass J. D., Dewey R., Chesebro B. Distinct HIV-1 env sequences are associated with neurotropism and neurovirulence. Curr Top Microbiol Immunol. 1995;202:89–104. doi: 10.1007/978-3-642-79657-9_7. [DOI] [PubMed] [Google Scholar]
  36. Power C., McArthur J. C., Johnson R. T., Griffin D. E., Glass J. D., Perryman S., Chesebro B. Demented and nondemented patients with AIDS differ in brain-derived human immunodeficiency virus type 1 envelope sequences. J Virol. 1994 Jul;68(7):4643–4649. doi: 10.1128/jvi.68.7.4643-4649.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Schuitemaker H., Koot M., Kootstra N. A., Dercksen M. W., de Goede R. E., van Steenwijk R. P., Lange J. M., Schattenkerk J. K., Miedema F., Tersmette M. 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 population. J Virol. 1992 Mar;66(3):1354–1360. doi: 10.1128/jvi.66.3.1354-1360.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Schuitemaker H., Kootstra N. A., de Goede R. E., de Wolf F., Miedema F., Tersmette M. Monocytotropic human immunodeficiency virus type 1 (HIV-1) variants detectable in all stages of HIV-1 infection lack T-cell line tropism and syncytium-inducing ability in primary T-cell culture. J Virol. 1991 Jan;65(1):356–363. doi: 10.1128/jvi.65.1.356-363.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. 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]
  40. Shioda T., Levy J. A., Cheng-Mayer C. 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. 1992 Oct 15;89(20):9434–9438. doi: 10.1073/pnas.89.20.9434. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Shpaer E. G., Delwart E. L., Kuiken C. L., Goudsmit J., Bachmann M. H., Mullins J. I. Conserved V3 loop sequences and transmission of human immunodeficiency virus type 1. AIDS Res Hum Retroviruses. 1994 Dec;10(12):1679–1684. doi: 10.1089/aid.1994.10.1679. [DOI] [PubMed] [Google Scholar]
  42. Tersmette M., Gruters R. A., de Wolf F., de Goede R. E., Lange J. M., Schellekens P. T., Goudsmit J., Huisman H. G., Miedema F. Evidence for a role of virulent human immunodeficiency virus (HIV) variants in the pathogenesis of acquired immunodeficiency syndrome: studies on sequential HIV isolates. J Virol. 1989 May;63(5):2118–2125. doi: 10.1128/jvi.63.5.2118-2125.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Tersmette M., de Goede R. E., Al B. J., Winkel I. N., Gruters R. A., Cuypers H. T., Huisman H. G., Miedema F. Differential syncytium-inducing capacity of human immunodeficiency virus isolates: frequent detection of syncytium-inducing isolates in patients with acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. J Virol. 1988 Jun;62(6):2026–2032. doi: 10.1128/jvi.62.6.2026-2032.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Toohey K., Wehrly K., Nishio J., Perryman S., Chesebro B. Human immunodeficiency virus envelope V1 and V2 regions influence replication efficiency in macrophages by affecting virus spread. Virology. 1995 Oct 20;213(1):70–79. doi: 10.1006/viro.1995.1547. [DOI] [PubMed] [Google Scholar]
  45. Westervelt P., Trowbridge D. B., Epstein L. G., Blumberg B. M., Li Y., Hahn B. H., Shaw G. M., Price R. W., Ratner L. Macrophage tropism determinants of human immunodeficiency virus type 1 in vivo. J Virol. 1992 Apr;66(4):2577–2582. doi: 10.1128/jvi.66.4.2577-2582.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Yamashita A., Yamamoto N., Matsuda J., Koyanagi Y. Cell type-specific heterogeneity of the HIV-1 V3 loop in infected individuals: selection of virus in macrophages and plasma. Virology. 1994 Oct;204(1):170–179. doi: 10.1006/viro.1994.1521. [DOI] [PubMed] [Google Scholar]
  47. Zhang L. Q., MacKenzie P., Cleland A., Holmes E. C., Brown A. J., Simmonds P. Selection for specific sequences in the external envelope protein of human immunodeficiency virus type 1 upon primary infection. J Virol. 1993 Jun;67(6):3345–3356. doi: 10.1128/jvi.67.6.3345-3356.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Zhu T., Mo H., Wang N., Nam D. S., Cao Y., Koup R. A., Ho D. D. Genotypic and phenotypic characterization of HIV-1 patients with primary infection. Science. 1993 Aug 27;261(5125):1179–1181. doi: 10.1126/science.8356453. [DOI] [PubMed] [Google Scholar]
  49. 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. Macrophage-tropic variants initiate human immunodeficiency virus type 1 infection after sexual, parenteral, and vertical transmission. J Clin Invest. 1994 Nov;94(5):2060–2067. doi: 10.1172/JCI117560. [DOI] [PMC free article] [PubMed] [Google Scholar]

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