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. 1996 Dec;70(12):8879–8887. doi: 10.1128/jvi.70.12.8879-8887.1996

Intrapatient sequence variation of the gag gene of human immunodeficiency virus type 1 plasma virions.

F K Yoshimura 1, K Diem 1, G H Learn Jr 1, S Riddell 1, L Corey 1
PMCID: PMC190985  PMID: 8971017

Abstract

Because certain regions of the gag gene, such as p24, are highly conserved among human immunodeficiency virus (HIV) isolates, many therapeutic strategies have been directed at gag gene targets. Although intrapatient variation of segments of gag have been determined, little is known about the variability of the full-length gag gene for HIV isolated from a single individual. To evaluate intrapatient full-length gag variability, we derived the nucleotide sequences of at least 10 cDNA gag clones of virion RNA isolated from plasma for each of four asymptomatic HIV type 1-infected patients with relatively high CD4+ T-cell counts (300 to 450 cells per mm3). Mean values of intrapatient gag nucleotide variation obtained by pairwise comparisons ranged from 0.55 to 2.86%. For three subjects, this value was equivalent to that reported for intrapatient full-length env variation. The greatest range of intrapatient mean nucleotide variation for individual protein-coding regions was observed for p7. We did not detect any G-to-A hypermutation, as A-to-G and G-to-A transitions occurred at similar frequencies, accounting for 29 and 25%, respectively, of the changes. Mean variation values and phylogenetic analysis suggested that the extent of nucleotide variation correlated with the length of viral infection. Furthermore, no distinct subpopulations of quasispecies were detectable within an individual. The predicted amino acid sequences indicated that there were no regions within a gag protein that were comprised of clustered changes.

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Selected References

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  1. Ahearne P. M., Matthews T. J., Lyerly H. K., White G. C., Bolognesi D. P., Weinhold K. J. Cellular immune response to viral peptides in patients exposed to HIV. AIDS Res Hum Retroviruses. 1988 Aug;4(4):259–267. doi: 10.1089/aid.1988.4.259. [DOI] [PubMed] [Google Scholar]
  2. Ahearne P. M., Morgan R. A., Sebastian M. W., Bolognesi D. P., Weinhold K. J. Multiple CTL specificities against autologous HIV-1-infected BLCLs. Cell Immunol. 1995 Mar;161(1):34–41. doi: 10.1006/cimm.1995.1006. [DOI] [PubMed] [Google Scholar]
  3. Albert J., Wahlberg J., Leitner T., Escanilla D., Uhlén M. Analysis of a rape case by direct sequencing of the human immunodeficiency virus type 1 pol and gag genes. J Virol. 1994 Sep;68(9):5918–5924. doi: 10.1128/jvi.68.9.5918-5924.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Balfe P., Simmonds P., Ludlam C. A., Bishop J. O., Brown A. J. Concurrent evolution of human immunodeficiency virus type 1 in patients infected from the same source: rate of sequence change and low frequency of inactivating mutations. J Virol. 1990 Dec;64(12):6221–6233. doi: 10.1128/jvi.64.12.6221-6233.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Brown A. L., Monaghan P. Evolution of the structural proteins of human immunodeficiency virus: selective constraints on nucleotide substitution. AIDS Res Hum Retroviruses. 1988 Dec;4(6):399–407. doi: 10.1089/aid.1988.4.399. [DOI] [PubMed] [Google Scholar]
  6. Burns D. P., Desrosiers R. C. Envelope sequence variation, neutralizing antibodies, and primate lentivirus persistence. Curr Top Microbiol Immunol. 1994;188:185–219. doi: 10.1007/978-3-642-78536-8_11. [DOI] [PubMed] [Google Scholar]
  7. Burns D. P., Desrosiers R. C. Selection of genetic variants of simian immunodeficiency virus in persistently infected rhesus monkeys. J Virol. 1991 Apr;65(4):1843–1854. doi: 10.1128/jvi.65.4.1843-1854.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Carmichael A., Jin X., Sissons P., Borysiewicz L. Quantitative analysis of the human immunodeficiency virus type 1 (HIV-1)-specific cytotoxic T lymphocyte (CTL) response at different stages of HIV-1 infection: differential CTL responses to HIV-1 and Epstein-Barr virus in late disease. J Exp Med. 1993 Feb 1;177(2):249–256. doi: 10.1084/jem.177.2.249. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Chargelegue D., Colvin B. T., O'Toole C. M. A 7-year analysis of anti-Gag (p17 and p24) antibodies in HIV-1-seropositive patients with haemophilia: immunoglobulin G titre and avidity are early predictors of clinical course. AIDS. 1993 Nov;7 (Suppl 2):S87–S90. doi: 10.1097/00002030-199311002-00017. [DOI] [PubMed] [Google Scholar]
  10. Dorfman T., Bukovsky A., Ohagen A., Höglund S., Göttlinger H. G. Functional domains of the capsid protein of human immunodeficiency virus type 1. J Virol. 1994 Dec;68(12):8180–8187. doi: 10.1128/jvi.68.12.8180-8187.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Fisher A. G., Collalti E., Ratner L., Gallo R. C., Wong-Staal F. A molecular clone of HTLV-III with biological activity. Nature. 1985 Jul 18;316(6025):262–265. doi: 10.1038/316262a0. [DOI] [PubMed] [Google Scholar]
  12. Forster S. M., Osborne L. M., Cheingsong-Popov R., Kenny C., Burnell R., Jeffries D. J., Pinching A. J., Harris J. R., Weber J. N. Decline of anti-p24 antibody precedes antigenaemia as correlate of prognosis in HIV-1 infection. AIDS. 1987 Dec;1(4):235–240. [PubMed] [Google Scholar]
  13. 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]
  14. Higgins D. G., Bleasby A. J., Fuchs R. CLUSTAL V: improved software for multiple sequence alignment. Comput Appl Biosci. 1992 Apr;8(2):189–191. doi: 10.1093/bioinformatics/8.2.189. [DOI] [PubMed] [Google Scholar]
  15. 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]
  16. Holmes E. C., Zhang L. Q., Robertson P., Cleland A., Harvey E., Simmonds P., Leigh Brown A. J. The molecular epidemiology of human immunodeficiency virus type 1 in Edinburgh. J Infect Dis. 1995 Jan;171(1):45–53. doi: 10.1093/infdis/171.1.45. [DOI] [PubMed] [Google Scholar]
  17. Holmes E. C., Zhang L. Q., Simmonds P., Rogers A. S., Brown A. J. Molecular investigation of human immunodeficiency virus (HIV) infection in a patient of an HIV-infected surgeon. J Infect Dis. 1993 Jun;167(6):1411–1414. doi: 10.1093/infdis/167.6.1411. [DOI] [PubMed] [Google Scholar]
  18. Kimura M. A simple method for estimating evolutionary rates of base substitutions through comparative studies of nucleotide sequences. J Mol Evol. 1980 Dec;16(2):111–120. doi: 10.1007/BF01731581. [DOI] [PubMed] [Google Scholar]
  19. Lange J. M., Paul D. A., Huisman H. G., de Wolf F., van den Berg H., Coutinho R. A., Danner S. A., van der Noordaa J., Goudsmit J. Persistent HIV antigenaemia and decline of HIV core antibodies associated with transition to AIDS. Br Med J (Clin Res Ed) 1986 Dec 6;293(6560):1459–1462. doi: 10.1136/bmj.293.6560.1459. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Louwagie J., McCutchan F. E., Peeters M., Brennan T. P., Sanders-Buell E., Eddy G. A., van der Groen G., Fransen K., Gershy-Damet G. M., Deleys R. Phylogenetic analysis of gag genes from 70 international HIV-1 isolates provides evidence for multiple genotypes. AIDS. 1993 Jun;7(6):769–780. doi: 10.1097/00002030-199306000-00003. [DOI] [PubMed] [Google Scholar]
  21. Mammano F., Ohagen A., Höglund S., Göttlinger H. G. Role of the major homology region of human immunodeficiency virus type 1 in virion morphogenesis. J Virol. 1994 Aug;68(8):4927–4936. doi: 10.1128/jvi.68.8.4927-4936.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Markham R. B., Yu X., Farzadegan H., Ray S. C., Vlahov D. Human immunodeficiency virus type 1 env and p17gag sequence variation in polymerase chain reaction-positive, seronegative injection drug users. J Infect Dis. 1995 Apr;171(4):797–804. doi: 10.1093/infdis/171.4.797. [DOI] [PubMed] [Google Scholar]
  23. McRae B., Lange J. A., Ascher M. S., de Wolf F., Sheppard H. W., Goudsmit J., Allain J. P. Immune response to HIV p24 core protein during the early phases of human immunodeficiency virus infection. AIDS Res Hum Retroviruses. 1991 Aug;7(8):637–643. doi: 10.1089/aid.1991.7.637. [DOI] [PubMed] [Google Scholar]
  24. Mehta S. U., Rupprecht K. R., Hunt J. C., Kramer D. E., McRae B. J., Allen R. G., Dawson G. J., Devare S. G. Prevalence of antibodies to the core protein P17, a serological marker during HIV-1 infection. AIDS Res Hum Retroviruses. 1990 Apr;6(4):443–454. doi: 10.1089/aid.1990.6.443. [DOI] [PubMed] [Google Scholar]
  25. Mulder-Kampinga G. A., Simonon A., Kuiken C. L., Dekker J., Scherpbier H. J., van de Perre P., Boer K., Goudsmit J. Similarity in env and gag genes between genomic RNAs of human immunodeficiency virus type 1 (HIV-1) from mother and infant is unrelated to time of HIV-1 RNA positivity in the child. J Virol. 1995 Apr;69(4):2285–2296. doi: 10.1128/jvi.69.4.2285-2296.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. 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]
  27. Nicholson J. K., Spira T. J., Aloisio C. H., Jones B. M., Kennedy M. S., Holman R. C., McDougal J. S. Serial determinations of HIV-1 titers in HIV-infected homosexual men: association of rising titers with CD4 T cell depletion and progression to AIDS. AIDS Res Hum Retroviruses. 1989 Apr;5(2):205–215. doi: 10.1089/aid.1989.5.205. [DOI] [PubMed] [Google Scholar]
  28. Nixon D. F., Townsend A. R., Elvin J. G., Rizza C. R., Gallwey J., McMichael A. J. HIV-1 gag-specific cytotoxic T lymphocytes defined with recombinant vaccinia virus and synthetic peptides. Nature. 1988 Dec 1;336(6198):484–487. doi: 10.1038/336484a0. [DOI] [PubMed] [Google Scholar]
  29. Overbaugh J., Rudensey L. M., Papenhausen M. D., Benveniste R. E., Morton W. R. Variation in simian immunodeficiency virus env is confined to V1 and V4 during progression to simian AIDS. J Virol. 1991 Dec;65(12):7025–7031. doi: 10.1128/jvi.65.12.7025-7031.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Pedersen C., Nielsen C. M., Vestergaard B. F., Gerstoft J., Krogsgaard K., Nielsen J. O. Temporal relation of antigenaemia and loss of antibodies to core antigens to development of clinical disease in HIV infection. Br Med J (Clin Res Ed) 1987 Sep 5;295(6598):567–569. doi: 10.1136/bmj.295.6598.567. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Pedroza Martins L., Chenciner N., Wain-Hobson S. Complex intrapatient sequence variation in the V1 and V2 hypervariable regions of the HIV-1 gp 120 envelope sequence. Virology. 1992 Dec;191(2):837–845. doi: 10.1016/0042-6822(92)90259-r. [DOI] [PubMed] [Google Scholar]
  32. Reicin A. S., Paik S., Berkowitz R. D., Luban J., Lowy I., Goff S. P. Linker insertion mutations in the human immunodeficiency virus type 1 gag gene: effects on virion particle assembly, release, and infectivity. J Virol. 1995 Feb;69(2):642–650. doi: 10.1128/jvi.69.2.642-650.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. 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]
  34. Sei Y., Tsang P. H., Roboz J. P., Sarin P. S., Wallace J. I., Bekesi J. G. Neutralizing antibodies as a prognostic indicator in the progression of acquired immune deficiency syndrome (AIDS)-related disorders: a double-blind study. J Clin Immunol. 1988 Nov;8(6):464–472. doi: 10.1007/BF00916952. [DOI] [PubMed] [Google Scholar]
  35. Simmonds P., Balfe P., Ludlam C. A., Bishop J. O., Brown A. J. Analysis of sequence diversity in hypervariable regions of the external glycoprotein of human immunodeficiency virus type 1. J Virol. 1990 Dec;64(12):5840–5850. doi: 10.1128/jvi.64.12.5840-5850.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Simmonds P., Zhang L. Q., McOmish F., Balfe P., Ludlam C. A., Brown A. J. Discontinuous sequence change of human immunodeficiency virus (HIV) type 1 env sequences in plasma viral and lymphocyte-associated proviral populations in vivo: implications for models of HIV pathogenesis. J Virol. 1991 Nov;65(11):6266–6276. doi: 10.1128/jvi.65.11.6266-6276.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Vartanian J. P., Meyerhans A., Asjö B., Wain-Hobson S. Selection, recombination, and G----A hypermutation of human immunodeficiency virus type 1 genomes. J Virol. 1991 Apr;65(4):1779–1788. doi: 10.1128/jvi.65.4.1779-1788.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Wang C. T., Barklis E. Assembly, processing, and infectivity of human immunodeficiency virus type 1 gag mutants. J Virol. 1993 Jul;67(7):4264–4273. doi: 10.1128/jvi.67.7.4264-4273.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. 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]
  40. Wills J. W., Craven R. C. Form, function, and use of retroviral gag proteins. AIDS. 1991 Jun;5(6):639–654. doi: 10.1097/00002030-199106000-00002. [DOI] [PubMed] [Google Scholar]
  41. Wolfs T. F., de Jong J. J., Van den Berg H., Tijnagel J. M., Krone W. J., Goudsmit J. Evolution of sequences encoding the principal neutralization epitope of human immunodeficiency virus 1 is host dependent, rapid, and continuous. Proc Natl Acad Sci U S A. 1990 Dec;87(24):9938–9942. doi: 10.1073/pnas.87.24.9938. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Wolinsky S. M., Wike C. M., Korber B. T., Hutto C., Parks W. P., Rosenblum L. L., Kunstman K. J., Furtado M. R., Muñoz J. L. Selective transmission of human immunodeficiency virus type-1 variants from mothers to infants. Science. 1992 Feb 28;255(5048):1134–1137. doi: 10.1126/science.1546316. [DOI] [PubMed] [Google Scholar]
  43. 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]
  44. 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]
  45. de Wolf F., Lange J. M., Houweling J. T., Coutinho R. A., Schellekens P. T., van der Noordaa J., Goudsmit J. Numbers of CD4+ cells and the levels of core antigens of and antibodies to the human immunodeficiency virus as predictors of AIDS among seropositive homosexual men. J Infect Dis. 1988 Sep;158(3):615–622. doi: 10.1093/infdis/158.3.615. [DOI] [PubMed] [Google Scholar]
  46. von Poblotzki A., Wagner R., Niedrig M., Wanner G., Wolf H., Modrow S. Identification of a region in the Pr55gag-polyprotein essential for HIV-1 particle formation. Virology. 1993 Apr;193(2):981–985. doi: 10.1006/viro.1993.1210. [DOI] [PubMed] [Google Scholar]

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