Population-specific evolution of HIV Gag epitopes in genetically diverged patients Syed H. Abidi a , Aniqa Shahid a , Laila S. Lakhani a , Muhammad R. Khanani b,c , Peter Ojwang d , Nancy Okinda d , Reena Shah g , Farhat Abbas e , Sarah Rowland-Jones f , Syed Ali a,b,⇑ a Department of Biological and Biomedical Sciences, Aga Khan University, Karachi, Pakistan b Dow University of Health Sciences, Karachi, Pakistan c Infection Control Society Pakistan, Karachi, Pakistan d Department of Pathology, Aga Khan University Hospital, Nairobi, Kenya e Department of Surgery, Aga Khan University, Karachi, Pakistan f MRC Human Immunology Unit, Oxford University, Oxford, UK g Department of Medicine, Aga Khan University, Nairobi, Kenya article info Article history: Received 19 November 2012 Received in revised form 30 January 2013 Accepted 3 February 2013 Available online 10 February 2013 Keywords: HIV Epitope Kenya Pakistan abstract Background: Under the host selection pressure HIV evolves rapidly to override crucial steps in the antigen presentation pathway. This allows the virus to escape binding and recognition by cytotoxic T lympho- cytes. Selection pressures on HIV can be unique depending on the immunogenetics of host populations. It is therefore logical to hypothesize that the virus evolving in a given population will carry signature mutations that will allow it to survive in that particular host milieu. Objectives: The aim of this study was to perform a comparative analysis of HIV-1 Gag subtype A sequences from two genetically diverged populations, namely, Kenyan and Pakistani. We analyzed unique mutations that could intercept the antigen processing pathway and potentially change the reper- toire of Gag epitopes in each study group. Methods: Twenty-nine Kenyan and 56 Pakistani samples from HIV-1 subtype A-infected patients were used in this study. The HIV-1 gag region p24 and p2p7p1p6 was sequenced and mutations affecting pro- teasomal degradation, TAP binding, HLA binding and CTL epitope generation, were analyzed using the in silico softwares NetChop and MAPPP, TAPPred, nHLAPred and CTLPred, respectively. Results: Certain mutations unique to either Pakistani or Kenyan patients were observed to affect sites for proteasomal degradation, TAP binding, and HLA binding. As a consequence of these mutations, epitope pattern in these populations was altered. Conclusion: Unique selection pressures can steer the direction of viral epitope evolution in the host pop- ulations. Population-specific HIV epitopes have to be taken into account while designing treatment as well as vaccine for HIV. Ó 2013 Elsevier B.V. All rights reserved. 1. Introduction Human Immunodeficiency Virus (HIV) is responsible for 33 mil- lion infections worldwide, and has claimed 25 million deaths in the past 30 years (Dieffenbach and Fauci, 2011). HIV-1 group M sub- types, A, B, C, D and CRF_AE have caused most HIV epidemics worldwide (http://www.hiv.lanl.gov). Cytotoxic T cell lymphocytes (CTLs) play a vital role in control- ling the HIV infection during both the acute and chronic phases. These cells are able to induce death on HIV-infected cells that dis- play the viral antigenic peptides on their surface (Peters et al., 2008). Generation of antigenic peptides is a multi-step process involving, (a) cleavage of HIV proteins by cellular proteasome machinery into peptides of varying lengths, (b) binding of these peptides with Transporter associated with Antigen Presentation (TAP) protein, (c) transport of the TAP-peptide complex through the endoplasmic reticulum to human leukocyte antigen (HLA) mol- ecules, and finally, (d) binding of HLA with the peptides and their display on the infected cell’s surface (Horst et al., 2009). HIV is a rapidly evolving virus. Under the host immunological pressures, HIV mutants amplify that have an advantage against host immunity (Brumme and Walker, 2009). These viral mutants predominantly express antigenic peptides that can override steps in the antigen presentation pathway namely proteasomal degrada- tion, TAP binding, HLA binding, and/or CTL recognition (Cardinaud et al., 2011; Tenzer et al., 2009). Antigen processing, thus dis- 1567-1348/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.meegid.2013.02.003 ⇑ Corresponding author. Address: Department of Biological and Biomedical Sciences, The Aga Khan University, P.O. Box 3500, Karachi 74800, Pakistan. Tel.: +92 21 486 4433. E-mail address: syed.ali@aku.edu (S. Ali). Infection, Genetics and Evolution 16 (2013) 78–86 Contents lists available at SciVerse ScienceDirect Infection, Genetics and Evolution journal homepage: www.elsevier.com/locate/meegid