Skip to main content
PMC home page
Journal of Virology logoLink to Journal of Virology
. 1997 Jun;71(6):4479–4484. doi: 10.1128/jvi.71.6.4479-4484.1997

Broad spectrum of in vivo fitness of human immunodeficiency virus type 1 subpopulations differing at reverse transcriptase codons 41 and 215.

J Goudsmit 1, A de Ronde 1, E de Rooij 1, R de Boer 1
PMCID: PMC191667  PMID: 9151839

Abstract

Viral populations in a human immunodeficiency virus type 1 (HIV-1)-infected individual behave as a quasispecies with a rated distribution of fitness variants. Fitness distributions in naturally occurring viral populations have been difficult to study due to the lack of markers for individual virus clones and complicating inter- and intrahost factors like the presence of multiple cell types with distinct tropisms, differences in route of transmission, and intervening immunity. Here, we quantitated the relative fitness in vivo of three subpopulations of HIV-1 marked by mutations at codons 41 and 215 of reverse transcriptase (RT) directly related to zidovudine resistance in an untreated individual who was infected by a zidovudine-resistant strain transmitted from a donor on therapy. The transmission event did not have a substantial impact on the distribution of mutants within the dominant virus population replicating to high levels in the recipient. The evolution of the RT gene was monitored for 20 months. All 102 clones obtained from the donor and the recipient at the different time points contained the M41L mutation, which is associated with a fourfold reduction in zidovudine sensitivity. The leucine at position 41 was stable, although it was encoded by TTG and CTG triplets that fluctuated in abundance partially due to founder effects of clones with nonsilent mutations at codon 215. Of the three subpopulations in the patient, distinguished by a tyrosine (TAC), aspartic acid (GAC), or serine (TCC) at the 215 position of RT, the relative fitness of the GAC variant was calculated to be 10 to 25% higher than the initial TAC variant, and the relative fitness of the TCC variant was 1% higher than that of the GAC variant. Similar to other RNA viruses, lentivirus populations like HIV-1 in patients with a high virus load apparently consist of a broader spectrum of fitness variants than the 1 to 2% fitness difference sufficient for significant replicative advantage.

Full Text

The Full Text of this article is available as a PDF (607.0 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Angarano G., Monno L., Appice A., Giannelli A., Romanelli C., Fico C., Pastore G. Transmission of zidovudine-resistant HIV-1 through heterosexual contacts. AIDS. 1994 Jul;8(7):1013–1014. doi: 10.1097/00002030-199407000-00023. [DOI] [PubMed] [Google Scholar]
  2. Boom R., Sol C. J., Salimans M. M., Jansen C. L., Wertheim-van Dillen P. M., van der Noordaa J. Rapid and simple method for purification of nucleic acids. J Clin Microbiol. 1990 Mar;28(3):495–503. doi: 10.1128/jcm.28.3.495-503.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Boucher C. A., O'Sullivan E., Mulder J. W., Ramautarsing C., Kellam P., Darby G., Lange J. M., Goudsmit J., Larder B. A. Ordered appearance of zidovudine resistance mutations during treatment of 18 human immunodeficiency virus-positive subjects. J Infect Dis. 1992 Jan;165(1):105–110. doi: 10.1093/infdis/165.1.105. [DOI] [PubMed] [Google Scholar]
  4. Boucher C. A., Tersmette M., Lange J. M., Kellam P., de Goede R. E., Mulder J. W., Darby G., Goudsmit J., Larder B. A. Zidovudine sensitivity of human immunodeficiency viruses from high-risk, symptom-free individuals during therapy. Lancet. 1990 Sep 8;336(8715):585–590. doi: 10.1016/0140-6736(90)93391-2. [DOI] [PubMed] [Google Scholar]
  5. 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]
  6. Chao L. Fitness of RNA virus decreased by Muller's ratchet. Nature. 1990 Nov 29;348(6300):454–455. doi: 10.1038/348454a0. [DOI] [PubMed] [Google Scholar]
  7. 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]
  8. Cornelissen M., Mulder-Kampinga G., Veenstra J., Zorgdrager F., Kuiken C., Hartman S., Dekker J., van der Hoek L., Sol C., Coutinho R. Syncytium-inducing (SI) phenotype suppression at seroconversion after intramuscular inoculation of a non-syncytium-inducing/SI phenotypically mixed human immunodeficiency virus population. J Virol. 1995 Mar;69(3):1810–1818. doi: 10.1128/jvi.69.3.1810-1818.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Duarte E. A., Novella I. S., Ledesma S., Clarke D. K., Moya A., Elena S. F., Domingo E., Holland J. J. Subclonal components of consensus fitness in an RNA virus clone. J Virol. 1994 Jul;68(7):4295–4301. doi: 10.1128/jvi.68.7.4295-4301.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Duarte E. A., Novella I. S., Weaver S. C., Domingo E., Wain-Hobson S., Clarke D. K., Moya A., Elena S. F., de la Torre J. C., Holland J. J. RNA virus quasispecies: significance for viral disease and epidemiology. Infect Agents Dis. 1994 Aug;3(4):201–214. [PubMed] [Google Scholar]
  11. Erice A., Mayers D. L., Strike D. G., Sannerud K. J., McCutchan F. E., Henry K., Balfour H. H., Jr Brief report: primary infection with zidovudine-resistant human immunodeficiency virus type 1. N Engl J Med. 1993 Apr 22;328(16):1163–1165. doi: 10.1056/NEJM199304223281605. [DOI] [PubMed] [Google Scholar]
  12. Goudsmit J., De Ronde A., Ho D. D., Perelson A. S. Human immunodeficiency virus fitness in vivo: calculations based on a single zidovudine resistance mutation at codon 215 of reverse transcriptase. J Virol. 1996 Aug;70(8):5662–5664. doi: 10.1128/jvi.70.8.5662-5664.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Hogervorst E., Jurriaans S., de Wolf F., van Wijk A., Wiersma A., Valk M., Roos M., van Gemen B., Coutinho R., Miedema F. Predictors for non- and slow progression in human immunodeficiency virus (HIV) type 1 infection: low viral RNA copy numbers in serum and maintenance of high HIV-1 p24-specific but not V3-specific antibody levels. J Infect Dis. 1995 Apr;171(4):811–821. doi: 10.1093/infdis/171.4.811. [DOI] [PubMed] [Google Scholar]
  14. Holland J. J., de la Torre J. C., Clarke D. K., Duarte E. Quantitation of relative fitness and great adaptability of clonal populations of RNA viruses. J Virol. 1991 Jun;65(6):2960–2967. doi: 10.1128/jvi.65.6.2960-2967.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Kellam P., Boucher C. A., Larder B. A. Fifth mutation in human immunodeficiency virus type 1 reverse transcriptase contributes to the development of high-level resistance to zidovudine. Proc Natl Acad Sci U S A. 1992 Mar 1;89(5):1934–1938. doi: 10.1073/pnas.89.5.1934. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Keulen W., Boucher C., Berkhout B. Nucleotide substitution patterns can predict the requirements for drug-resistance of HIV-1 proteins. Antiviral Res. 1996 Jun;31(1-2):45–57. doi: 10.1016/0166-3542(96)00944-8. [DOI] [PubMed] [Google Scholar]
  17. Larder B. A., Darby G., Richman D. D. HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy. Science. 1989 Mar 31;243(4899):1731–1734. doi: 10.1126/science.2467383. [DOI] [PubMed] [Google Scholar]
  18. Mellors J. W., Kingsley L. A., Rinaldo C. R., Jr, Todd J. A., Hoo B. S., Kokka R. P., Gupta P. Quantitation of HIV-1 RNA in plasma predicts outcome after seroconversion. Ann Intern Med. 1995 Apr 15;122(8):573–579. doi: 10.7326/0003-4819-122-8-199504150-00003. [DOI] [PubMed] [Google Scholar]
  19. Mellors J. W., Rinaldo C. R., Jr, Gupta P., White R. M., Todd J. A., Kingsley L. A. Prognosis in HIV-1 infection predicted by the quantity of virus in plasma. Science. 1996 May 24;272(5265):1167–1170. doi: 10.1126/science.272.5265.1167. [DOI] [PubMed] [Google Scholar]
  20. Mohri H., Singh M. K., Ching W. T., Ho D. D. Quantitation of zidovudine-resistant human immunodeficiency virus type 1 in the blood of treated and untreated patients. Proc Natl Acad Sci U S A. 1993 Jan 1;90(1):25–29. doi: 10.1073/pnas.90.1.25. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. 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]
  22. Nijhuis M., Boucher C. A., Schuurman R. Sensitive procedure for the amplification of HIV-1 RNA using a combined reverse-transcription and amplification reaction. Biotechniques. 1995 Aug;19(2):178-80, 182. [PubMed] [Google Scholar]
  23. Novella I. S., Clarke D. K., Quer J., Duarte E. A., Lee C. H., Weaver S. C., Elena S. F., Moya A., Domingo E., Holland J. J. Extreme fitness differences in mammalian and insect hosts after continuous replication of vesicular stomatitis virus in sandfly cells. J Virol. 1995 Nov;69(11):6805–6809. doi: 10.1128/jvi.69.11.6805-6809.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Novella I. S., Elena S. F., Moya A., Domingo E., Holland J. J. Size of genetic bottlenecks leading to virus fitness loss is determined by mean initial population fitness. J Virol. 1995 May;69(5):2869–2872. doi: 10.1128/jvi.69.5.2869-2872.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Nájera I., Holguín A., Quiñones-Mateu M. E., Muñoz-Fernández M. A., Nájera R., López-Galíndez C., Domingo E. Pol gene quasispecies of human immunodeficiency virus: mutations associated with drug resistance in virus from patients undergoing no drug therapy. J Virol. 1995 Jan;69(1):23–31. doi: 10.1128/jvi.69.1.23-31.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Perelson A. S., Neumann A. U., Markowitz M., Leonard J. M., Ho D. D. HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time. Science. 1996 Mar 15;271(5255):1582–1586. doi: 10.1126/science.271.5255.1582. [DOI] [PubMed] [Google Scholar]
  27. Wahlberg J., Fiore J., Angarano G., Uhlén M., Albert J. Apparent selection against transmission of zidovudine-resistant human immunodeficiency virus type 1 variants. J Infect Dis. 1994 Mar;169(3):611–614. doi: 10.1093/infdis/169.3.611. [DOI] [PubMed] [Google Scholar]
  28. de Jong M. D., Veenstra J., Stilianakis N. I., Schuurman R., Lange J. M., de Boer R. J., Boucher C. A. Host-parasite dynamics and outgrowth of virus containing a single K70R amino acid change in reverse transcriptase are responsible for the loss of human immunodeficiency virus type 1 RNA load suppression by zidovudine. Proc Natl Acad Sci U S A. 1996 May 28;93(11):5501–5506. doi: 10.1073/pnas.93.11.5501. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. de Wolf F., Goudsmit J., Paul D. A., Lange J. M., Hooijkaas C., Schellekens P., Coutinho R. A., van der Noordaa J. Risk of AIDS related complex and AIDS in homosexual men with persistent HIV antigenaemia. Br Med J (Clin Res Ed) 1987 Sep 5;295(6598):569–572. doi: 10.1136/bmj.295.6598.569. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. van Gemen B., Kievits T., Schukkink R., van Strijp D., Malek L. T., Sooknanan R., Huisman H. G., Lens P. Quantification of HIV-1 RNA in plasma using NASBA during HIV-1 primary infection. J Virol Methods. 1993 Jul;43(2):177–187. doi: 10.1016/0166-0934(93)90075-3. [DOI] [PubMed] [Google Scholar]
  31. van den Hoek J. A., Coutinho R. A., van Haastrecht H. J., van Zadelhoff A. W., Goudsmit J. Prevalence and risk factors of HIV infections among drug users and drug-using prostitutes in Amsterdam. AIDS. 1988 Feb;2(1):55–60. doi: 10.1097/00002030-198802000-00010. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Virology are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES