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Journal of Virology, February 2008, p. 1980-1992, Vol. 82, No. 4
0022-538X/08/$08.00+0     doi:10.1128/JVI.02742-06
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

An Integrative Bioinformatic Approach for Studying Escape Mutations in Human Immunodeficiency Virus Type 1 gag in the Pumwani Sex Worker Cohort{triangledown}

Harold O. Peters,1,{dagger} Mark G. Mendoza,1,{dagger} Rupert E. Capina,1,{dagger} Ma Luo,1* Xiaojuan Mao,1 Michael Gubbins,2 Nico J. D. Nagelkerke,4 Ian MacArthur,2 Brent B. Sheardown,2 Joshua Kimani,3 Charles Wachihi,3 Subo Thavaneswaran,1 and Francis A. Plummer1,2

Department of Medical Microbiology, University of Manitoba, 730 William Avenue, Winnipeg, Manitoba, Canada,1 Public Health Agency of Canada, Winnipeg, Manitoba, Canada,2 Department of Medical Microbiology, University of Nairobi, Nairobi, Kenya,3 Department of Community Medicine, UAE University, P.O. Box 17666, Al Ain, United Arab Emirates4

Received 13 December 2006/ Accepted 2 November 2007

Human immunodeficiency virus type 1 (HIV-1) is able to evade the host cytotoxic T-lymphocyte (CTL) response through a variety of escape avenues. Epitopes that are presented to CTLs are first processed in the presenting cell in several steps, including proteasomal cleavage, transport to the endoplasmic reticulum, binding by the HLA molecule, and finally presentation to the T-cell receptor. An understanding of the potential of the virus to escape CTL responses can aid in designing an effective vaccine. To investigate such a potential, we analyzed HIV-1 gag from 468 HIV-1-positive Kenyan women by using several bioinformatic approaches that allowed the identification of positively selected amino acids in the HIV-1 gag region and study of the effects that these mutations could have on the various stages of antigen processing. Correlations between positively selected residues and mean CD4 counts also allowed study of the effect of mutation on HIV disease progression. A number of mutations that could create or destroy proteasomal cleavage sites or reduce binding affinity of the transport antigen processing protein, effectively hindering epitope presentation, were identified. Many mutations correlated with the presence of specific HLA alleles and with lower or higher CD4 counts. For instance, the mutation V190I in subtype A1-infected individuals is associated with HLA-B*5802 (P = 4.73 x 10–4), a rapid-progression allele according to other studies, and also to a decreased mean CD4 count (P = 0.019). Thus, V190I is a possible HLA escape mutant. This method classifies many positively selected mutations across the entire gag region according to their potential for immune escape and their effect on disease progression.

* Corresponding author. Mailing address: National Microbiology Laboratory, 1015 Arlington St., Winnipeg, Manitoba R3E 3R2, Canada. Phone: (204) 789-6074. Fax: (204) 789-2018. E-mail: ma_luo{at}phac-aspc.gc.ca

{triangledown} Published ahead of print on 5 December 2007.

{dagger} H.O.P., M.G.M., and R.E.C. made equal contributions to the work.

Journal of Virology, February 2008, p. 1980-1992, Vol. 82, No. 4
0022-538X/08/$08.00+0     doi:10.1128/JVI.02742-06
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • McKinnon, L. R., Capina, R., Peters, H., Mendoza, M., Kimani, J., Wachihi, C., Kariri, A., Kimani, M., Richmond, M., Kiazyk, S. K., Fowke, K. R., Jaoko, W., Luo, M., Ball, T. B., Plummer, F. A. (2009). Clade-Specific Evolution Mediated by HLA-B*57/5801 in Human Immunodeficiency Virus Type 1 Clade A1 p24. J. Virol. 83: 12636-12642 [Abstract] [Full Text]  


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