Abstract
In order to develop a better understanding of the evolutionary dynamics of HIV drug resistance, it is necessary to quantify accurately the in vivo fitness costs of resistance mutations. However, the reliable estimation of such fitness costs is riddled with both theoretical and experimental difficulties. Experimental fitness assays typically suffer from the shortcoming that they are based on in vitro data. Fitness estimates based on the mathematical analysis of in vivo data, however, are often questionable because the underlying assumptions are not fulfilled. In particular, the assumption that the replication rate of the virus population is constant in time is frequently grossly violated. By extending recent work of Marée and colleagues, we present here a new approach that corrects for time-dependent viral replication in time-series data for growth competition of mutants. This approach allows a reliable estimation of the relative replicative capacity (with confidence intervals) of two competing virus variants growing within the same patient, using longitudinal data for the total plasma virus load, the relative frequency of the two variants and the death rate of infected cells. We assess the accuracy of our method using computer-generated data. An implementation of the developed method is freely accessible on the Web (http://www.eco.ethz.ch/fitness.html).
Full Text
The Full Text of this article is available as a PDF (186.2 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Bonhoeffer S., May R. M., Shaw G. M., Nowak M. A. Virus dynamics and drug therapy. Proc Natl Acad Sci U S A. 1997 Jun 24;94(13):6971–6976. doi: 10.1073/pnas.94.13.6971. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bonhoeffer S., Nowak M. A. Pre-existence and emergence of drug resistance in HIV-1 infection. Proc Biol Sci. 1997 May 22;264(1382):631–637. doi: 10.1098/rspb.1997.0089. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Borrow P., Lewicki H., Wei X., Horwitz M. S., Peffer N., Meyers H., Nelson J. A., Gairin J. E., Hahn B. H., Oldstone M. B. Antiviral pressure exerted by HIV-1-specific cytotoxic T lymphocytes (CTLs) during primary infection demonstrated by rapid selection of CTL escape virus. Nat Med. 1997 Feb;3(2):205–211. doi: 10.1038/nm0297-205. [DOI] [PubMed] [Google Scholar]
- 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]
- 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]
- Croteau G., Doyon L., Thibeault D., McKercher G., Pilote L., Lamarre D. Impaired fitness of human immunodeficiency virus type 1 variants with high-level resistance to protease inhibitors. J Virol. 1997 Feb;71(2):1089–1096. doi: 10.1128/jvi.71.2.1089-1096.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Eastman P. S., Mittler J., Kelso R., Gee C., Boyer E., Kolberg J., Urdea M., Leonard J. M., Norbeck D. W., Mo H. Genotypic changes in human immunodeficiency virus type 1 associated with loss of suppression of plasma viral RNA levels in subjects treated with ritonavir (Norvir) monotherapy. J Virol. 1998 Jun;72(6):5154–5164. doi: 10.1128/jvi.72.6.5154-5164.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- Goudsmit J., de Ronde A., de Rooij E., de Boer R. Broad spectrum of in vivo fitness of human immunodeficiency virus type 1 subpopulations differing at reverse transcriptase codons 41 and 215. J Virol. 1997 Jun;71(6):4479–4484. doi: 10.1128/jvi.71.6.4479-4484.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Goulder P. J., Brander C., Tang Y., Tremblay C., Colbert R. A., Addo M. M., Rosenberg E. S., Nguyen T., Allen R., Trocha A. Evolution and transmission of stable CTL escape mutations in HIV infection. Nature. 2001 Jul 19;412(6844):334–338. doi: 10.1038/35085576. [DOI] [PubMed] [Google Scholar]
- Goulder P. J., Phillips R. E., Colbert R. A., McAdam S., Ogg G., Nowak M. A., Giangrande P., Luzzi G., Morgan B., Edwards A. Late escape from an immunodominant cytotoxic T-lymphocyte response associated with progression to AIDS. Nat Med. 1997 Feb;3(2):212–217. doi: 10.1038/nm0297-212. [DOI] [PubMed] [Google Scholar]
- Harrigan P. R., Bloor S., Larder B. A. Relative replicative fitness of zidovudine-resistant human immunodeficiency virus type 1 isolates in vitro. J Virol. 1998 May;72(5):3773–3778. doi: 10.1128/jvi.72.5.3773-3778.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- Ho D. D., Toyoshima T., Mo H., Kempf D. J., Norbeck D., Chen C. M., Wideburg N. E., Burt S. K., Erickson J. W., Singh M. K. Characterization of human immunodeficiency virus type 1 variants with increased resistance to a C2-symmetric protease inhibitor. J Virol. 1994 Mar;68(3):2016–2020. doi: 10.1128/jvi.68.3.2016-2020.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- 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]
- Larder B. A., Kemp S. D. Multiple mutations in HIV-1 reverse transcriptase confer high-level resistance to zidovudine (AZT). Science. 1989 Dec 1;246(4934):1155–1158. doi: 10.1126/science.2479983. [DOI] [PubMed] [Google Scholar]
- Mansky L. M. Forward mutation rate of human immunodeficiency virus type 1 in a T lymphoid cell line. AIDS Res Hum Retroviruses. 1996 Mar 1;12(4):307–314. doi: 10.1089/aid.1996.12.307. [DOI] [PubMed] [Google Scholar]
- Martinez-Picado J., Savara A. V., Shi L., Sutton L., D'Aquila R. T. Fitness of human immunodeficiency virus type 1 protease inhibitor-selected single mutants. Virology. 2000 Sep 30;275(2):318–322. doi: 10.1006/viro.2000.0527. [DOI] [PubMed] [Google Scholar]
- Martinez-Picado J., Savara A. V., Sutton L., D'Aquila R. T. Replicative fitness of protease inhibitor-resistant mutants of human immunodeficiency virus type 1. J Virol. 1999 May;73(5):3744–3752. doi: 10.1128/jvi.73.5.3744-3752.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Martínez M. A., Carrillo C., González-Candelas F., Moya A., Domingo E., Sobrino F. Fitness alteration of foot-and-mouth disease virus mutants: measurement of adaptability of viral quasispecies. J Virol. 1991 Jul;65(7):3954–3957. doi: 10.1128/jvi.65.7.3954-3957.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nowak M. A., Bonhoeffer S., Hill A. M., Boehme R., Thomas H. C., McDade H. Viral dynamics in hepatitis B virus infection. Proc Natl Acad Sci U S A. 1996 Apr 30;93(9):4398–4402. doi: 10.1073/pnas.93.9.4398. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nowak M. A., Bonhoeffer S., Loveday C., Balfe P., Semple M., Kaye S., Tenant-Flowers M., Tedder R. HIV results in the frame. Results confirmed. Nature. 1995 May 18;375(6528):193–193. doi: 10.1038/375193a0. [DOI] [PubMed] [Google Scholar]
- 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]
- 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]
- Ramratnam B., Bonhoeffer S., Binley J., Hurley A., Zhang L., Mittler J. E., Markowitz M., Moore J. P., Perelson A. S., Ho D. D. Rapid production and clearance of HIV-1 and hepatitis C virus assessed by large volume plasma apheresis. Lancet. 1999 Nov 20;354(9192):1782–1785. doi: 10.1016/S0140-6736(99)02035-8. [DOI] [PubMed] [Google Scholar]
- Ribeiro R. M., Bonhoeffer S., Nowak M. A. The frequency of resistant mutant virus before antiviral therapy. AIDS. 1998 Mar 26;12(5):461–465. doi: 10.1097/00002030-199805000-00006. [DOI] [PubMed] [Google Scholar]
- Ribeiro R. M., Bonhoeffer S. Production of resistant HIV mutants during antiretroviral therapy. Proc Natl Acad Sci U S A. 2000 Jul 5;97(14):7681–7686. doi: 10.1073/pnas.97.14.7681. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Richman D. D., Havlir D., Corbeil J., Looney D., Ignacio C., Spector S. A., Sullivan J., Cheeseman S., Barringer K., Pauletti D. Nevirapine resistance mutations of human immunodeficiency virus type 1 selected during therapy. J Virol. 1994 Mar;68(3):1660–1666. doi: 10.1128/jvi.68.3.1660-1666.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Richman D. D. Zidovudine resistance of human immunodeficiency virus. Rev Infect Dis. 1990 Jul-Aug;12 (Suppl 5):S507–S512. doi: 10.1093/clinids/12.supplement_5.s507. [DOI] [PubMed] [Google Scholar]
- St Clair M. H., Martin J. L., Tudor-Williams G., Bach M. C., Vavro C. L., King D. M., Kellam P., Kemp S. D., Larder B. A. Resistance to ddI and sensitivity to AZT induced by a mutation in HIV-1 reverse transcriptase. Science. 1991 Sep 27;253(5027):1557–1559. doi: 10.1126/science.1716788. [DOI] [PubMed] [Google Scholar]
- 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]
- Yuste E., Sánchez-Palomino S., Casado C., Domingo E., López-Galíndez C. Drastic fitness loss in human immunodeficiency virus type 1 upon serial bottleneck events. J Virol. 1999 Apr;73(4):2745–2751. doi: 10.1128/jvi.73.4.2745-2751.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zennou V., Mammano F., Paulous S., Mathez D., Clavel F. Loss of viral fitness associated with multiple Gag and Gag-Pol processing defects in human immunodeficiency virus type 1 variants selected for resistance to protease inhibitors in vivo. J Virol. 1998 Apr;72(4):3300–3306. doi: 10.1128/jvi.72.4.3300-3306.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]