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 Google Scholar
Google Scholar
Right arrow Articles by Wick, W. D.
Right arrow Articles by Yang, O. O.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Wick, W. D.
Right arrow Articles by Yang, O. O.

 Previous Article  |  Next Article 

Journal of Virology, March 2009, p. 2349-2356, Vol. 83, No. 5
0022-538X/09/$08.00+0     doi:10.1128/JVI.00821-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Predicting the Impact of Blocking Human Immunodeficiency Virus Type 1 Nef In Vivo{triangledown}

W. David Wick,1* Peter B. Gilbert,1 and Otto O. Yang2

Vaccine and Infectious Disease Institute, Fred Hutchinson Cancer Research Center, Seattle, Washington,1 UCLA AIDS Institute, Department of Medicine, Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, UCLA, Los Angeles, California2

Received 16 April 2008/ Accepted 6 October 2008

Human immunodeficiency virus type 1 (HIV-1) Nef is a multifunctional protein that confers an ability to evade killing by cytotoxic T lymphocytes (CTLs) as well as other advantages to the virus in vivo. Here we exploited mathematical modeling and related statistical methods to estimate the impact of Nef activity on viral replication in vivo in relation to CTLs. Our results indicate that downregulation of major histocompatibility complex class I (MHC-I) A and B by wild-type Nef confers an advantage to the virus of about 82% in decreased CTL killing efficiency on average, meaning that abolishing the MHC-I downregulation function of Nef would increase killing by more than fivefold. We incorporated this estimate, as well as prior estimates of replicative enhancement by Nef, into a previously published model of HIV-1 and CTLs in vivo (W. D. Wick, O. O. Yang, L. Corey, and S. G. Self, J. Virol. 79:13579-13586, 2005), generalized to permit CTL recognition of multiple epitopes. A sequence database analysis revealed that 92.9% of HIV-1 epitopes are A or B restricted, and a previous study found an average of about 19 epitopes recognized (M. M. Addo et al., J. Virol. 77:2081-2092, 2003). We combined these estimates in the model in order to predict the impact of inhibiting Nef function in the general (chronically infected) population by a drug. The predicted impact on viral load ranged from negligible to 2.4 orders of magnitude, depending on the effects of the drug and the CTL dynamical scenario assumed. We conclude that inhibiting Nef could make a substantial reduction in disease burden, lengthening the time before the necessity of undertaking combination therapy with other antiretroviral drugs.

* Corresponding author. Mailing address: Fred Hutchinson Cancer Research Center, M2-C200, 1100 Fairview Ave. N, Seattle, WA 98109-1024. Phone: (206) 667-7980. Fax: (206) 667-4812. E-mail: wick{at}scharp.org

{triangledown} Published ahead of print on 17 December 2008.

Journal of Virology, March 2009, p. 2349-2356, Vol. 83, No. 5
0022-538X/09/$08.00+0     doi:10.1128/JVI.00821-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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