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Conquering the AIDS epidemic remains one of the most challenging global health issues. Despite impressive advances in combination antiretroviral therapy (cART) to treat HIV, and substantial progress in the development of prevention interventions, a protective vaccine has remained elusive. Successful vaccination will require the immune system to function better than it does in natural infection, in which the infection invariably becomes chronic. However, there are a very small number of patients termed “elite controllers” who become infected but can control viremia, with the preponderance of evidence pointing to CD8 T cell mediated immune control. The existence of such patients implies that the human immune system, although not able to eradicate infection, is potentially capable of durable control of HIV-1 and prevention of HIV-associated disease [reviewed in (Deeks and Walker, 2007; Walker and Yu, 2013)]. The beauty of Major Histocompatibility Complex (MHC)restriction in T cell immunity is that within a population, there may always be individuals who bear particular MHC alleles, able to present antigenic peptides derived from invading pathogens for T cell receptors (TCRs) to recognize. This ultimately gives rise to effective cellular immunity to control chronic infection to save the species (Zinkernagel and Doherty, 1997). This has been exemplified by the global HIV1 epidemic. The above-mentioned “elite controllers” (as opposed to progressors) are enriched in expression of certain “protective” class I Human Leukocyte Antigen (HLA) alleles such as HLA-B*57/5801 subtypes and B*27. By contrast, other persons who express so-called deleterious or disease susceptible alleles, including HLA-B*18/53 are much more likely to develop AIDS in the absence of cART (O’Brien et al., 2001). Obviously, the differential peptide presentation by HLA molecules is rooted in host MHC polymorphism. Indeed, a genome-wide association study (GWAS) clearly demonstrated that specific amino acid variations in the peptide-binding groove are associated with host control of HIV-1 infection (Pereyra et al., 2010). Therefore, unraveling the molecular mechanism of host control of HIV-1 infection by cellular immunity is extremely important for eventually devising a strategy to eliminate the HIV-1 epidemic. To begin to address the structural basis for Tcell mediated control of HIV, we initiated a structural analysis of an immunodominant CD8 T cell epitope QW9 (QASQEVKNW, p24 residues 176–184) from HIV-1 bound to the restricting HLA class I molecule B*5801. This epitope is of particular interest because the conserved Gag protein forms the essential capsid of HIV-1 (Zhao et al., 2013), with mutations likely to impose a fitness cost. In addition, QW9 can be presented by a spectrum of HLA molecules for comparative investigation (Buseyne et al., 2001; Buseyne et al., 1997; Currier et al., 2005; Kloverpris et al., 2013). Here, we report the first crystal structures of HLA-B*5801, one of the most HIV-protective HLA molecules, loaded with QW9 and its natural variants QW9-S3T and QW9-E5D. All three structures are in a very similar crystal lattice and have two independent molecules in one asymmetric unit. Fig. 1A is the overall view of one of the QW9wt/HLA-B*5801 complexes in crystal structure. The most interesting feature of these three QW9/HLA-B*5801 complex structures is that the conformation of the middle portion of the bound peptide appears varied (Fig. 1B), even between the two independent molecules in the same crystal structure (Fig. 1C–E). It is not uncommon to have a highly exposed residue at the center of the presenting peptide on the HLA molecule to have its side chain flexible (Ladell et al., 2013). Our unique observation is that among these six QW9/HLA complexes in three crystal structures, the peptide residue K7 can be modeled outwards in two cases (Fig. 1C for QW9wt-1 and Fig. 1D for QW9E5D-2), but buried inwards in another two cases (Fig. 1C for QW9wt-2 and Fig. 1E for QW9-S3T-2). It should be emphasized that despite the weak density of the long and floppy side chain, the density for the main chain conformation and the Cα-Cβ direction of the K7 residue in Fig. 1C–E is actually convincing enough for the assignment of its side chain to be outwards (convex-shaped main chain in Fig. 1C for QW9wt-1 and Fig. 1D for QW9-E5D-2) or inwards (concave-shaped main chain in Fig. 1C for QW9wt-2 and Fig. 1E for QW9-E5D-2). The above structural data imply that unlike those anchoring residues (W9 in QW9 as a typical example, see Fig. 1B), the conformation of the central protruding residues, K7 in particular, can actually be in a dynamic distribution. This is probably because the whole protruding and mobile

Crystal structure of HLA-B*5801, a protective HLA allele for HIV-1 infection