Original Article CD8 + T-cell Cytotoxic Capacity Associated with Human Immunodeficiency Virus-1 Control Can Be Mediated through Various Epitopes and Human Leukocyte Antigen Types Stephen A. Migueles a,1 , Daniel Mendoza a,1 , Matthew G. Zimmerman a , Kelly M. Martins a , Sushila A. Toulmin a , Elizabeth P. Kelly a , Bennett A. Peterson a , Sarah A. Johnson a , Eric Galson a , Kate O. Poropatich a , Andy Patamawenu a , Hiromi Imamichi a , Alexander Ober a , Catherine A. Rehm a , Sara Jones b , Claire W. Hallahan c , Dean A. Follmann c , Mark Connors a, ⁎ a Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA b Clinical Monitoring Research Program, Leidos Biomedical Research, Inc., Frederick, MD, USA c Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA abstract article info Article history: Received 13 November 2014 Received in revised form 18 December 2014 Accepted 19 December 2014 Available online 22 December 2014 Keywords: Long-term nonprogressors/elite controllers Immune control CD8 + T cells Cytotoxic capacity Epitope specificity Understanding natural immunologic control over Human Immunodeficiency Virus (HIV)-1 replication, as occurs in rare long-term nonprogressors/elite controllers (LTNP/EC), should inform the design of efficacious HIV vac- cines and immunotherapies. Durable control in LTNP/EC is likely mediated by highly functional virus-specific CD8 + T-cells. Protective Human Leukocyte Antigen (HLA) class I alleles, like B*27 and B*57, are present in most, but not all LTNP/EC, providing an opportunity to investigate features shared by their HIV-specific immune responses. To better understand the contribution of epitope targeting and conservation to immune control, we compared the CD8 + T-cell specificity and function of B*27/57 neg LTNP/EC (n = 23), B*27/57 pos LTNP/EC (n = 23) and B*27/57 neg progressors (n = 13). Fine mapping revealed 11 previously unreported immunodominant re- sponses. Although B*27/57 neg LTNP/EC did not target more highly conserved epitopes, their CD8 + T-cell cytotoxic capacity was significantly higher than progressors. Similar to B*27/57 pos LTNP/EC, this superior cytotoxicity was mediated by preferential expansion of immunodominant responses and lysis through the predicted HLA. These findings suggest that increased CD8 + T-cell cytotoxic capacity is a common mechanism of control in most LTNP/EC regardless of HLA type. They also suggest that potent cytotoxicity can be mediated through various epitopes and HLA molecules and could, in theory, be induced in most people. Published by Elsevier B.V. 1. Introduction Investigations performed in long-term nonprogressors/elite controllers (LTNP/EC) have provided considerable insights into the mechanisms underlying durable control over HIV replication. Strong associations have been identified between this phenotype and particular Major Histocompatibility Complex (MHC) class I alleles, especially B*27 and B*57 (Kaslow et al., 1996; Migueles and Connors, 2010; Migueles et al., 2000). A similar phenotype has been found in Simian Immunodefi- ciency Virus (SIV)-infected Rhesus macaques and is associated with Mamu B*8 and B*17 (Loffredo et al., 2007; Yant et al., 2006). It has been suggested that these protective alleles mediate their effect by presenting peptides whose sequences are conserved due to structural or functional constraints on the virus (Allen et al., 2005; Brockman et al., 2007; Crawford et al., 2007; Friedrich et al., 2004; Goulder et al., 1997; Leslie et al., 2004; Pereyra et al., 2014; Peyerl et al., 2004). In some studies of progressors, focused targeting by HIV-specific CD8 + T-cell responses of more conserved regions has been associated with lower HIV RNA levels (Dinges et al., 2010; Kunwar et al., 2013; Liu et al., 2009; Mothe et al., 2011). Although the role of epitope conservation in the effect of MHC on HIV control among progressors is not yet clear, it appears less likely that it differen- tiates progressors from LTNP/EC bearing protective alleles. In larger groups of B*57 pos patients that include true LTNP/EC, the prevalence of epitope sequence variations was comparable between LTNP/EC and progressors (Bailey et al., 2006; Migueles et al., 2003; Miura et al., 2009). In both groups, the CD8 + T-cell response targets epitopes restricted by these protective class I proteins (Altfeld et al., 2003; EBioMedicine 2 (2015) 46–58 ⁎ Corresponding author at: HIV-Specific Immunity Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, NIH, Building 10, Room 11B-07, 10 Center Drive, Bethesda, MD 20892, USA. E-mail address: mconnors@niaid.nih.gov (M. Connors). 1 These authors contributed equally to this work. http://dx.doi.org/10.1016/j.ebiom.2014.12.009 2352-3964/Published by Elsevier B.V. Contents lists available at ScienceDirect EBioMedicine journal homepage: www.ebiomedicine.com