br Financial Disclosures br Author Contributions br Role of

Financial Disclosures
Author Contributions
Role of Funding Source
Acknowledgments We acknowledge Brain Resource as the sponsor for the iSPOT-D study (NCT00693849). Claire Day and Catherine King (Global Study Co-ordinators) are thanked as is the iSPOT-D Publication Team for their valuable input into this manuscript and to the study overall. We acknowledge the hard work of the Brain Dynamics Centre iSPOT-D team at the Sydney site for their help with data collection of the presented cohort. Dr Anthony Harris is thanked for his role in clinical supervision of clinical imaging evaluations (as PI for the Sydney site), and Dr Tim Usherwood for his role in overseeing the partnership with primary care practitioners and recruitment of patients from these primary care settings (as co-PI for the Sydney site). Dr Lavier Gomes, Ms Sheryl Foster and the Department of Radiology at Westmead are thanked for their substantial contributions to MRI data acquisition. SMG acknowledges the support of the Sydney Medical School Foundation.
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 Immunodeficiency 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 soluble guanylate cyclase 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 differentiates progressors from LTNP/EC bearing protective alleles. In larger groups of 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; Goulder et al., 1996; Migueles et al., 2000). Nonetheless, most HIV-infected individuals bearing protective alleles experience progressive infection. This suggests that protective genotypes and preferential epitope targeting are clearly not sufficient for high-level HIV control and do not distinguish LTNP/EC from progressors bearing protective alleles (Bailey et al., 2006; Migueles et al., 2000, 2003; Miura et al., 2009). In contrast, there is a growing consensus that durable control among patients bearing protective alleles is associated with superior CD8+ T-cell function (reviewed in Hersperger et al., 2011). Among the CD8+ T-cell functions that have most consistently distinguished LTNP/EC from progressors are increased polyfunctionality, proliferation, loading of cytotoxic proteins, virus suppressive ability and cytotoxic capacity (Betts et al., 2006; Ferre et al., 2009; Hersperger et al., 2010; Migueles et al., 2002, 2008; Saez-Cirion et al., 2007; Zimmerli et al., 2005). Similarly, there is some evidence of better CD8+ T-cell functionality in LTNP/EC macaques compared to progressors (Mendoza et al., 2013).