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. 1997 Jul;71(7):4871–4881. doi: 10.1128/jvi.71.7.4871-4881.1997

In vivo sequence variability of human immunodeficiency virus type 1 envelope gp120: association of V2 extension with slow disease progression.

T Shioda 1, S Oka 1, X Xin 1, H Liu 1, R Harukuni 1, A Kurotani 1, M Fukushima 1, M K Hasan 1, T Shiino 1, Y Takebe 1, A Iwamoto 1, Y Nagai 1
PMCID: PMC191717  PMID: 9188549

Abstract

According to the rate of depletion of CD4 cell counts, we grouped 12 cases of human immunodeficiency virus type 1 (HIV-1) infection as 6 rapid (21.0 to 33.8 cells per microl per month) and 6 slow (0.9 to 7.9 cells per microl per month) progressors and determined the individual viral quasispecies patterns by sequencing the genome region encoding the V1, V2, and V3 loops of envelope protein. Although the quasispecies structures varied widely from one individual to another, a strong correlation was observed between a low rate of disease progression and a high degree of genetic diversity of HIV-1. Furthermore, the V2 loop extension was observed specifically in individuals with slow or no disease progression, whereas basic amino acid substitutions in V3 characteristic of a viral phenotype shift from non-syncytium inducing to syncytium inducing were observed in patients with advanced stages of disease regardless of their rate of disease progression. Studies with recombinant viruses suggested that elongation of V2 potentially restricts the capacity of HIV-1 to replicate in macrophages. Thus, our results suggest the association of distinct sequence features of both V3 and V2 with particular patterns of disease progression. Elongation of the V2 loop may be a good predictor of slow disease progression, while basic substitutions of V3 without elongation of V2 are characteristic of rapid progression.

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Selected References

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  1. 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]
  2. Cao Y., Qin L., Zhang L., Safrit J., Ho D. D. Virologic and immunologic characterization of long-term survivors of human immunodeficiency virus type 1 infection. N Engl J Med. 1995 Jan 26;332(4):201–208. doi: 10.1056/NEJM199501263320401. [DOI] [PubMed] [Google Scholar]
  3. 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]
  4. 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]
  5. Connor R. I., Mohri H., Cao Y., Ho D. D. Increased viral burden and cytopathicity correlate temporally with CD4+ T-lymphocyte decline and clinical progression in human immunodeficiency virus type 1-infected individuals. J Virol. 1993 Apr;67(4):1772–1777. doi: 10.1128/jvi.67.4.1772-1777.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cornelissen M., Hogervorst E., Zorgdrager F., Hartman S., Goudsmit J. Maintenance of syncytium-inducing phenotype of HIV type 1 is associated with positively charged residues in the HIV type 1 gp120 V2 domain without fixed positions, elongation, or relocated N-linked glycosylation sites. AIDS Res Hum Retroviruses. 1995 Oct;11(10):1169–1175. doi: 10.1089/aid.1995.11.1169. [DOI] [PubMed] [Google Scholar]
  7. Costagliola D., Mary J. Y., Brouard N., Laporte A., Valleron A. J. Incubation time for AIDS from French transfusion-associated cases. Nature. 1989 Apr 27;338(6218):768–769. doi: 10.1038/338768a0. [DOI] [PubMed] [Google Scholar]
  8. 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]
  9. Dean M., Carrington M., Winkler C., Huttley G. A., Smith M. W., Allikmets R., Goedert J. J., Buchbinder S. P., Vittinghoff E., Gomperts E. Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Hemophilia Growth and Development Study, Multicenter AIDS Cohort Study, Multicenter Hemophilia Cohort Study, San Francisco City Cohort, ALIVE Study. Science. 1996 Sep 27;273(5283):1856–1862. doi: 10.1126/science.273.5283.1856. [DOI] [PubMed] [Google Scholar]
  10. Embretson J., Zupancic M., Ribas J. L., Burke A., Racz P., Tenner-Racz K., Haase A. T. Massive covert infection of helper T lymphocytes and macrophages by HIV during the incubation period of AIDS. Nature. 1993 Mar 25;362(6418):359–362. doi: 10.1038/362359a0. [DOI] [PubMed] [Google Scholar]
  11. 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]
  12. Goodenow M., Huet T., Saurin W., Kwok S., Sninsky J., Wain-Hobson S. HIV-1 isolates are rapidly evolving quasispecies: evidence for viral mixtures and preferred nucleotide substitutions. J Acquir Immune Defic Syndr. 1989;2(4):344–352. [PubMed] [Google Scholar]
  13. 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]
  14. Ho D. D., Neumann A. U., Perelson A. S., Chen W., Leonard J. M., Markowitz M. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature. 1995 Jan 12;373(6510):123–126. doi: 10.1038/373123a0. [DOI] [PubMed] [Google Scholar]
  15. 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]
  16. Keet I. P., Krol A., Klein M. R., Veugelers P., de Wit J., Roos M., Koot M., Goudsmit J., Miedema F., Coutinho R. A. Characteristics of long-term asymptomatic infection with human immunodeficiency virus type 1 in men with normal and low CD4+ cell counts. J Infect Dis. 1994 Jun;169(6):1236–1243. doi: 10.1093/infdis/169.6.1236. [DOI] [PubMed] [Google Scholar]
  17. 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]
  18. Koito A., Stamatatos L., Cheng-Mayer C. Small amino acid sequence changes within the V2 domain can affect the function of a T-cell line-tropic human immunodeficiency virus type 1 envelope gp120. Virology. 1995 Feb 1;206(2):878–884. doi: 10.1006/viro.1995.1010. [DOI] [PubMed] [Google Scholar]
  19. Koot M., Keet I. P., Vos A. H., de Goede R. E., Roos M. T., Coutinho R. A., Miedema F., Schellekens P. T., Tersmette M. Prognostic value of HIV-1 syncytium-inducing phenotype for rate of CD4+ cell depletion and progression to AIDS. Ann Intern Med. 1993 May 1;118(9):681–688. doi: 10.7326/0003-4819-118-9-199305010-00004. [DOI] [PubMed] [Google Scholar]
  20. Learmont J., Tindall B., Evans L., Cunningham A., Cunningham P., Wells J., Penny R., Kaldor J., Cooper D. A. Long-term symptomless HIV-1 infection in recipients of blood products from a single donor. Lancet. 1992 Oct 10;340(8824):863–867. doi: 10.1016/0140-6736(92)93281-q. [DOI] [PubMed] [Google Scholar]
  21. Liu R., Paxton W. A., Choe S., Ceradini D., Martin S. R., Horuk R., MacDonald M. E., Stuhlmann H., Koup R. A., Landau N. R. Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell. 1996 Aug 9;86(3):367–377. doi: 10.1016/s0092-8674(00)80110-5. [DOI] [PubMed] [Google Scholar]
  22. Lui K. J., Darrow W. W., Rutherford G. W., 3rd A model-based estimate of the mean incubation period for AIDS in homosexual men. Science. 1988 Jun 3;240(4857):1333–1335. doi: 10.1126/science.3163848. [DOI] [PubMed] [Google Scholar]
  23. Lukashov V. V., Kuiken C. L., Goudsmit J. Intrahost human immunodeficiency virus type 1 evolution is related to length of the immunocompetent period. J Virol. 1995 Nov;69(11):6911–6916. doi: 10.1128/jvi.69.11.6911-6916.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Masuda T., Matsushita S., Kuroda M. J., Kannagi M., Takatsuki K., Harada S. Generation of neutralization-resistant HIV-1 in vitro due to amino acid interchanges of third hypervariable env region. J Immunol. 1990 Nov 15;145(10):3240–3246. [PubMed] [Google Scholar]
  25. McKeating J. A., Gow J., Goudsmit J., Pearl L. H., Mulder C., Weiss R. A. Characterization of HIV-1 neutralization escape mutants. AIDS. 1989 Dec;3(12):777–784. doi: 10.1097/00002030-198912000-00001. [DOI] [PubMed] [Google Scholar]
  26. Meyerhans A., Cheynier R., Albert J., Seth M., Kwok S., Sninsky J., Morfeldt-Månson L., Asjö B., Wain-Hobson S. Temporal fluctuations in HIV quasispecies in vivo are not reflected by sequential HIV isolations. Cell. 1989 Sep 8;58(5):901–910. doi: 10.1016/0092-8674(89)90942-2. [DOI] [PubMed] [Google Scholar]
  27. Moss A. R., Bacchetti P. Natural history of HIV infection. AIDS. 1989 Feb;3(2):55–61. doi: 10.1097/00002030-198902000-00001. [DOI] [PubMed] [Google Scholar]
  28. Mulder J., McKinney N., Christopherson C., Sninsky J., Greenfield L., Kwok S. Rapid and simple PCR assay for quantitation of human immunodeficiency virus type 1 RNA in plasma: application to acute retroviral infection. J Clin Microbiol. 1994 Feb;32(2):292–300. doi: 10.1128/jcm.32.2.292-300.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Nei M., Gojobori T. Simple methods for estimating the numbers of synonymous and nonsynonymous nucleotide substitutions. Mol Biol Evol. 1986 Sep;3(5):418–426. doi: 10.1093/oxfordjournals.molbev.a040410. [DOI] [PubMed] [Google Scholar]
  30. Nowak M. A., Anderson R. M., McLean A. R., Wolfs T. F., Goudsmit J., May R. M. Antigenic diversity thresholds and the development of AIDS. Science. 1991 Nov 15;254(5034):963–969. doi: 10.1126/science.1683006. [DOI] [PubMed] [Google Scholar]
  31. Oka S., Ida S., Shioda T., Takebe Y., Kobayashi N., Shibuya Y., Ohyama K., Momota K., Kimura S., Shimada K. Genetic analysis of HIV-1 during rapid progression to AIDS in an apparently healthy man. AIDS Res Hum Retroviruses. 1994 Mar;10(3):271–277. doi: 10.1089/aid.1994.10.271. [DOI] [PubMed] [Google Scholar]
  32. Ou C. Y., Takebe Y., Weniger B. G., Luo C. C., Kalish M. L., Auwanit W., Yamazaki S., Gayle H. D., Young N. L., Schochetman G. Independent introduction of two major HIV-1 genotypes into distinct high-risk populations in Thailand. Lancet. 1993 May 8;341(8854):1171–1174. doi: 10.1016/0140-6736(93)91001-3. [DOI] [PubMed] [Google Scholar]
  33. Page R. D. TreeView: an application to display phylogenetic trees on personal computers. Comput Appl Biosci. 1996 Aug;12(4):357–358. doi: 10.1093/bioinformatics/12.4.357. [DOI] [PubMed] [Google Scholar]
  34. Pantaleo G., Graziosi C., Demarest J. F., Butini L., Montroni M., Fox C. H., Orenstein J. M., Kotler D. P., Fauci A. S. HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease. Nature. 1993 Mar 25;362(6418):355–358. doi: 10.1038/362355a0. [DOI] [PubMed] [Google Scholar]
  35. Paxton W. A., Martin S. R., Tse D., O'Brien T. R., Skurnick J., VanDevanter N. L., Padian N., Braun J. F., Kotler D. P., Wolinsky S. M. Relative resistance to HIV-1 infection of CD4 lymphocytes from persons who remain uninfected despite multiple high-risk sexual exposure. Nat Med. 1996 Apr;2(4):412–417. doi: 10.1038/nm0496-412. [DOI] [PubMed] [Google Scholar]
  36. Phillips R. E., Rowland-Jones S., Nixon D. F., Gotch F. M., Edwards J. P., Ogunlesi A. O., Elvin J. G., Rothbard J. A., Bangham C. R., Rizza C. R. Human immunodeficiency virus genetic variation that can escape cytotoxic T cell recognition. Nature. 1991 Dec 12;354(6353):453–459. doi: 10.1038/354453a0. [DOI] [PubMed] [Google Scholar]
  37. Preston B. D., Poiesz B. J., Loeb L. A. Fidelity of HIV-1 reverse transcriptase. Science. 1988 Nov 25;242(4882):1168–1171. doi: 10.1126/science.2460924. [DOI] [PubMed] [Google Scholar]
  38. Richman D. D., Bozzette S. A. The impact of the syncytium-inducing phenotype of human immunodeficiency virus on disease progression. J Infect Dis. 1994 May;169(5):968–974. doi: 10.1093/infdis/169.5.968. [DOI] [PubMed] [Google Scholar]
  39. Roberts J. D., Bebenek K., Kunkel T. A. The accuracy of reverse transcriptase from HIV-1. Science. 1988 Nov 25;242(4882):1171–1173. doi: 10.1126/science.2460925. [DOI] [PubMed] [Google Scholar]
  40. Saitou N., Nei M. The neighbor-joining method: a new method for reconstructing phylogenetic trees. Mol Biol Evol. 1987 Jul;4(4):406–425. doi: 10.1093/oxfordjournals.molbev.a040454. [DOI] [PubMed] [Google Scholar]
  41. Samson M., Libert F., Doranz B. J., Rucker J., Liesnard C., Farber C. M., Saragosti S., Lapoumeroulie C., Cognaux J., Forceille C. Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature. 1996 Aug 22;382(6593):722–725. doi: 10.1038/382722a0. [DOI] [PubMed] [Google Scholar]
  42. Schuitemaker H., Fouchier R. A., Broersen S., Groenink M., Koot M., van 't Wout A. B., Huisman H. G., Tersmette M., Miedema F. Envelope V2 configuration and HIV-1 phenotype: clarification. Science. 1995 Apr 7;268(5207):115–115. doi: 10.1126/science.7755774. [DOI] [PubMed] [Google Scholar]
  43. 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]
  44. 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]
  45. Shioda T., Oka S., Ida S., Nokihara K., Toriyoshi H., Mori S., Takebe Y., Kimura S., Shimada K., Nagai Y. A naturally occurring single basic amino acid substitution in the V3 region of the human immunodeficiency virus type 1 env protein alters the cellular host range and antigenic structure of the virus. J Virol. 1994 Dec;68(12):7689–7696. doi: 10.1128/jvi.68.12.7689-7696.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. 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]
  47. Tersmette M., Lange J. M., de Goede R. E., de Wolf F., Eeftink-Schattenkerk J. K., Schellekens P. T., Coutinho R. A., Huisman J. G., Goudsmit J., Miedema F. Association between biological properties of human immunodeficiency virus variants and risk for AIDS and AIDS mortality. Lancet. 1989 May 6;1(8645):983–985. doi: 10.1016/s0140-6736(89)92628-7. [DOI] [PubMed] [Google Scholar]
  48. Thompson J. D., Higgins D. G., Gibson T. J. CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res. 1994 Nov 11;22(22):4673–4680. doi: 10.1093/nar/22.22.4673. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. 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]
  50. Wang N., Zhu T., Ho D. D. Sequence diversity of V1 and V2 domains of gp120 from human immunodeficiency virus type 1: lack of correlation with viral phenotype. J Virol. 1995 Apr;69(4):2708–2715. doi: 10.1128/jvi.69.4.2708-2715.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Wei X., Ghosh S. K., Taylor M. E., Johnson V. A., Emini E. A., Deutsch P., Lifson J. D., Bonhoeffer S., Nowak M. A., Hahn B. H. Viral dynamics in human immunodeficiency virus type 1 infection. Nature. 1995 Jan 12;373(6510):117–122. doi: 10.1038/373117a0. [DOI] [PubMed] [Google Scholar]
  52. 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]
  53. Willey R. L., Smith D. H., Lasky L. A., Theodore T. S., Earl P. L., Moss B., Capon D. J., Martin M. A. In vitro mutagenesis identifies a region within the envelope gene of the human immunodeficiency virus that is critical for infectivity. J Virol. 1988 Jan;62(1):139–147. doi: 10.1128/jvi.62.1.139-147.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Wolinsky S. M., Korber B. T., Neumann A. U., Daniels M., Kunstman K. J., Whetsell A. J., Furtado M. R., Cao Y., Ho D. D., Safrit J. T. Adaptive evolution of human immunodeficiency virus-type 1 during the natural course of infection. Science. 1996 Apr 26;272(5261):537–542. doi: 10.1126/science.272.5261.537. [DOI] [PubMed] [Google Scholar]
  55. Zinkernagel R. M., Hengartner H. T-cell-mediated immunopathology versus direct cytolysis by virus: implications for HIV and AIDS. Immunol Today. 1994 Jun;15(6):262–268. doi: 10.1016/0167-5699(94)90005-1. [DOI] [PubMed] [Google Scholar]

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