This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Rouzine, I. M.
Right arrow Articles by Coffin, J. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Rouzine, I. M.
Right arrow Articles by Coffin, J. M.

 Previous Article  |  Next Article 

Journal of Virology, October 1999, p. 8167-8178, Vol. 73, No. 10
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Search for the Mechanism of Genetic Variation in the pro Gene of Human Immunodeficiency Virus

I. M. Rouzine* and J. M. Coffin

Department of Molecular Biology and Microbiology, School of Medicine, Tufts University, Boston, Massachusetts 02111

Received 24 February 1999/Accepted 23 June 1999

To study the mechanism of evolution of the human immunodeficiency virus (HIV) protease gene (pro), we analyzed a database of 213 pro sequences isolated from 11 HIV type 1-infected patients who had not been treated with protease inhibitors. Variation in pro is restricted to rare variable bases which are highly diverse and differ in location among individuals; an average variable base appears in about 16% of individuals. The average intrapatient distance per individual variable site, 27%, is similar for synonymous and nonsynonymous sites, although synonymous sites are twice as abundant. The latter observation excludes selection for diversity as an important, permanently acting factor in the evolution of pro and leaves purifying selection as the only kind of selection. Based on this, we developed a model of evolution, both within individuals and along the transmission chain, which explains variable sites as slightly deleterious mutants slowly reverting to the better-fit variant during individual infection. In the case of a single-source transmission, genetic bottlenecks at the moment of transmission effectively suppress selection, allowing mutants to accumulate along the transmission chain to high levels. However, even very rare coinfections from independent sources are, as we show, able to counteract the bottleneck effect. Therefore, there are two possible explanations for the high mutant frequency. First, the frequency of coinfection in the natural host population may be quite low. Alternatively, a strong variation of the best-adapted sequence between individuals could be caused by a combination of an immune response present in early infection and coselection.

* Corresponding author. Mailing address: Department of Molecular Biology and Microbiology, School of Medicine, Tufts University, 136 Harrison Ave., Boston, MA 02111. Phone: (617) 636-0917. Fax: (617) 636-4086. E-mail: irouzine{at}emerald.tufts.edu.

Journal of Virology, October 1999, p. 8167-8178, Vol. 73, No. 10
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Fernandez, G., Clotet, B., Martinez, M. A. (2007). Fitness Landscape of Human Immunodeficiency Virus Type 1 Protease Quasispecies. J. Virol. 81: 2485-2496 [Abstract] [Full Text]  
  • Rouzine, I. M., Coffin, J. M. (2005). Evolution of Human Immunodeficiency Virus Under Selection and Weak Recombination. Genetics 170: 7-18 [Abstract] [Full Text]  
  • Hue, S., Pillay, D., Clewley, J. P., Pybus, O. G. (2005). Genetic analysis reveals the complex structure of HIV-1 transmission within defined risk groups. Proc. Natl. Acad. Sci. USA 102: 4425-4429 [Abstract] [Full Text]  
  • Lu, X., Yu, Q., Binder, G. K., Chen, Z., Slepushkina, T., Rossi, J., Dropulic, B. (2004). Antisense-Mediated Inhibition of Human Immunodeficiency Virus (HIV) Replication by Use of an HIV Type 1-Based Vector Results in Severely Attenuated Mutants Incapable of Developing Resistance. J. Virol. 78: 7079-7088 [Abstract] [Full Text]  
  • Kapoor, A., Jones, M., Shafer, R. W., Rhee, S.-Y., Kazanjian, P., Delwart, E. L. (2004). Sequencing-Based Detection of Low-Frequency Human Immunodeficiency Virus Type 1 Drug-Resistant Mutants by an RNA/DNA Heteroduplex Generator-Tracking Assay. J. Virol. 78: 7112-7123 [Abstract] [Full Text]  
  • Rouzine, I. M., Wakeley, J., Coffin, J. M. (2003). The solitary wave of asexual evolution. Proc. Natl. Acad. Sci. USA 100: 587-592 [Abstract] [Full Text]  
  • Whitney, J. B., Oliveira, M., Detorio, M., Guan, Y., Wainberg, M. A. (2002). The M184V Mutation in Reverse Transcriptase Can Delay Reversion of Attenuated Variants of Simian Immunodeficiency Virus. J. Virol. 76: 8958-8962 [Abstract] [Full Text]  
  • Rouzine, I. M., Rodrigo, A., Coffin, J. M. (2001). Transition between Stochastic Evolution and Deterministic Evolution in the Presence of Selection: General Theory and Application to Virology. Microbiol. Mol. Biol. Rev. 65: 151-185 [Abstract] [Full Text]  
  • Ikuta, K., Suzuki, S., Horikoshi, H., Mukai, T., Luftig, R. B. (2000). Positive and Negative Aspects of the Human Immunodeficiency Virus Protease: Development of Inhibitors versus Its Role in AIDS Pathogenesis. Microbiol. Mol. Biol. Rev. 64: 725-745 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»