Impact of MHC class I diversity on immune control of immunodeficiency virus replication

Abstract

The recent failure of the T-cell-based HIV vaccine trial led by Merck & Co., Inc. prompts the urgent need to refocus on the question of which T-cell responses are required to control HIV replication. The well-described association between the expression of particular MHC class I molecules and successful containment of HIV or, in the macaque model, SIV replication provide a valuable starting point from which to evaluate more precisely what might constitute effective CD8(+) T-cell responses. Here, we review recent studies of T-cell-mediated control of HIV and SIV infection, and offer insight for the design of a successful T-cell-based HIV vaccine in the future.

Figure 1. Diverse distribution of HLA-B alleles worldwide

HLA class I diversity is illustrated by the prevalence of nine HLA-B molecules in eight selected populations (see the allele frequencies website). For simplicity, HLA class I alleles are shown by two digits only.

Figure 2. Diversity of amino acids at position 2 in optimal peptides that bind HLA-A, HLA-B and HLA-C

Amino acids have been grouped into the following categories: amino acids with hydroxyl-containing side chains (Thr, Ser); small-to-medium sized hydrophobic residues (Gly, Ala, Val, Leu, Ile, Met); amino acids with a cyclic side chain (Pro); amino acids with aromatic side chains (Phe, Tyr, Trp); amino acids with acidic side chains (Asp, Glu); amino acids with basic side chains (His, Lys, Arg); amino acids with amide side chains (Gln). Peptides that bind to HLA-A alleles are almost exclusively restricted to those that have hydrophobic or hydroxyl-containing residues at position 2, whereas HLA-B-binding peptides include these and peptides with proline, charged residues or glutamine at position 2. HLA-C-binding peptides are less diverse than HLA-B-binding peptides, but they are more closely related to HLA-B than HLA-A in their peptide-binding motif. Data taken from REFS ,.

Figure 3. Schematic model of immune control of HIV mediated by HLA alleles presenting multiple gag epitopes

In HIV-infected individuals with HLA class I alleles that are associated with effective control of the virus (such as HLA-B57 and HLA-B27), Gag-specific responses are generated in acute infection. Wild-type virus-specific-cytotoxic T lymphocytes (CTLs) recognize virus-infected cells early in the viral life cycle, before Nef-mediated MHC class I downregulation. Escape mutations that are typically selected in Gag reduce in vitro viral fitness. Remaining wild-type virus-specific CTL responses can contain the infection until new escape variants are selected. However, increasing numbers of costly escape mutations further limit the replicative capacity of the virus, thereby facilitating effective killing of virus-infected cells by remaining CTLs. TCR, T-cell receptor.