The human MHC region, located on the short arm of chromosome 6, is central to the immune response, as it encodes proteins that help to distinguish between self and non-self protein components. Of the three MHC class I loci in humans (HLA-A, HLA-B and HLA-C), HLA-B is the most polymorphic, with 817 different HLA-B molecules described, compared to 486 distinct HLA-A and 263 distinct HLA-C molecules (see the IMGT/HLA database). Indeed, HLA-B is the most polymorphic locus on chromosome 6 and in the entire human genome18
. Differences in the frequency of various HLA-B alleles in selected populations worldwide are shown in to illustrate the extraordinary diversity of distinct human populations with respect to HLA allele expression.
Diverse distribution of HLA-B alleles worldwide
Almost all of this extensive HLA class I polymorphism is restricted to those residues that line the peptide-binding groove of these molecules19
, thereby defining the peptides that bind to each HLA molecule. The significance of HLA class I polymorphism is that the differences among the various HLA molecules and the peptides they present are of sufficient functional importance to be subject to Darwinian natural selection: in short, these differences are a matter of life and death. Seemingly insignificant, single amino-acid differences between closely related HLA alleles may have crucial consequences in terms of outcome from particular infections. In the setting of HIV infection, examples include the association of HLA-B*3502 and HLA-B*3503 with rapid disease progression, and a lack of any such association for HLA-B*3501, which differs from HLA-B*3502 and HLA-B*3503 by only three and one amino acid, respectively20–22
. These small changes would be expected to affect the binding of the C-terminal amino acid of the peptide to the F pocket of the HLA molecule: the preferred residue for binding to the F pocket of HLA-B*3501 is tyrosine23
, whereas a smaller hydrophobic residue is preferred for binding to the F pocket of HLA-B*3502 and of HLA-B*3503 (REFS 19,22
). This therefore affects the binding of peptides such as the HLA-B*3501-restricted epitope of Gag p24, PPIPVGEIY (Gag residues 254–262), to HLA-B*3502 and HLA-B*3503. The observed differences in Gag-specific CD8+
T-cell responses between HLA-B*3501-, HLA-B*3502- and HLA-B*3503- positive study subjects24
are therefore not unexpected, and if Gag is an important target for immune control of HIV17
, such HLA differences may be of crucial importance. In a more extreme example, a study of HIV infection in Durban, South Africa, found a strong association between HLA-B*5801 and low viral load, whereas HLA-B*5802, which differs from HLA-B*5801 by three amino acids, was associated with high viral load16
. Again, these few differences between apparently closely related HLA class I molecules translate into substantial differences in peptide-binding specificity19
Scrutiny of the peptides presented by superficially similar HLA class I molecules invariably reveals subtle but important differences. One study of five closely-related HLA alleles within the HLA-B7 supertype (HLA-B*0702, HLA-B*3910, HLA-B*4201, HLA-B*4202 and HLA-B*8101) demonstrated that, even when an identical peptide is presented by distinct alleles, different selection pressure can be imposed on the virus25
. As described above, this result should not be unexpected because the very existence of HLA class I polymorphism is strong evidence that meaningful differences in disease outcome result from it.
The HLA class I alleles that have been identified consistently to have a significant impact on the rate of disease progression, or on viral setpoint (which is strongly predictive of the rate of disease progression16,26–34
) are shown in . MHC class I molecules that are associated with successful control of SIV infection, as shown in studies of the SIV-macaque model of HIV infection, are also included35–48
. It is evident that in HIV infection, HLA-B molecules have the strongest impact on viral setpoint compared with HLA-A and HLA-C molecules16
for reasons that remain unclear. A more diverse selection of peptide-binding motifs is offered by HLA-B alleles compared with HLA-A alleles, as illustrated by the residues at position 2 (P2) of the 100 optimally defined HIV epitopes that were most strongly targeted by CD8+
T cells in a recent large population-based study17
(). In particular, proline is frequently an anchor-binding residue at P2 in HLA-B-binding peptides, which also include peptides with charged residues at P2.
Strong MHC class I associations with particular outcome of HIV or SIV infection
Diversity of amino acids at position 2 in optimal peptides that bind HLA-A, HLA-B and HLA-C
It is noteworthy that Mamu-B*08 and Mamu-B*17, two rhesus macaque MHC class I alleles that are associated with the control of SIV replication36,37,40
, have peptide-binding motifs that in some respects resemble those of the two HLA class I molecules most consistently associated with control of HIV infection, HLA-B*27 (which binds peptides with an arginine at P2) and HLA-B*57 (which binds peptides with a tryp-tophan at the C terminus), respectively19
. Indeed, the eight currently known Mamu-B*08-restricted CD8+
T-cell epitopes fit the peptide-binding requirements defined for HLA-B*27 (REF. 48
), and peptides that bind to HLA-B*27 also bind to Mamu-B*08 with high affinity (J. T. Loffredo, unpublished observations). Interestingly, most of the HLA-B*27- and Mamu-B*08-restricted T-cell responses are directed towards peptides with two arginine residues at the N terminus (that is, at P1 and P2). It has recently been suggested that peptides with di-basic N termini are resistant to peptidase degradation, thereby increasing their intracellular half-lives. So, fewer molecules of the target antigen may be required to generate the necessary HLA-B*27- and Mamu-B*08-bound peptides to trigger CTL recognition and responses.
Despite the homology between SIV and HIV, there are no viral epitopes that are common targets of the CTL response in both HLA-B*27-positive humans and Mamu-B*08-positive macaques. However, the Gag epitope TSTLQEQIAW (which is abbreviated as TW10 and corresponds to the Gag amino acids 240–249) is the main target of the acute CD8+
T-cell response in HIV-infected subjects who have HLA-B*57 or HLA-B*5801 and is very similar to the SIV homologue (SSVDEQIQW, Gag 241–249) presented by the Mamu-A*90120-5 class I molecule, which is also associated with control of SIV in Burmese macaques42
. The Gag epitope KAFSPEVIPMF (KF11, Gag 162–172), which is the dominant focus of the CD8+
T-cell response in HLA-B*57-positive subjects with chronic HIV infection17
overlaps with the SIV epitope KKFGAEVVP (KP9, Gag 162–170) presented by Mane-A*10, an MHC class I molecule that is associated with the control of SIV infection in pigtail macaques46,47
. So, certain MHC class I molecules associated with the control of HIV replication in humans and SIV replication in macaque models can have similar or dissimilar peptide-binding motifs that nonetheless enable peptides from the same regions of particular viral proteins to be targeted by CD8+