Control of HIV-1 viremia and protection from AIDS are associated with HLA-Bw4 homozygosity

Abstract

Certain HLA-B antigens have been associated with lack of progression to AIDS. HLA-B alleles can be divided into two mutually exclusive groups based on the expression of the molecular epitopes HLA-Bw4 and HLA-Bw6. Notably, in addition to its role in presenting viral peptides for immune recognition, the HLA-Bw4, but not HLA-Bw6, motif functions as a ligand for a natural killer cell inhibitory receptor (KIR). Here, we show that profound suppression of HIV-1 viremia is significantly associated with homozygosity for HLA-B alleles that share the HLA-Bw4 epitope. Furthermore, homozygosity for HLA-Bw4 alleles was also significantly associated with the ability to remain AIDS free and to maintain a normal CD4 T cell count in a second cohort of HIV-1-infected individuals with well defined dates of seroconversion. This association was independent of the presence of a mutation in CC chemokine receptor 5 (CCR5) associated with resistance to HIV-1 infection, and it was independent of the presence of HLA alleles that could potentially confound the results. We conclude that homozygosity for HLA-Bw4-bearing B alleles is associated with a significant advantage and that the HLA-Bw4 motif is important in AIDS pathogenesis.

The beneficial impact of missing KIR ligands and absence of donor KIR2DS3 gene on outcome following unrelated hematopoietic SCT for myeloid leukemia in the Chinese population

“…Accordingly, some clinical data have confirmed that NK cell alloreactivity in the graft vs host (GVH) direction can reduce relapse rate and prolong OS after HSCT in patients with AML, 1,2,9 chronic myeloid leukemia (CML), 9,10 myelodysplastic syndrome (MDS) 9 and childhood acute lymphoid leukemia (ALL). 1 However, other studies have arrived at the opposite conclusion, particularly in unrelated donor HSCT (URD-HSCT), and have shown a deleterious effect of NK cell alloreactivity. 11 Natural killer cell alloreactivity (see above) was based on the KIR ligand mismatch model, also known as the ligandligand model.…”

“…Apart from alloreactive T cells, alloreactive natural killer (NK) cells also have an important role in the induction of a GVL effect after HSCT. 1,2 Natural killer cells possess the ability to kill cells that are undergoing tumorigenesis or infection by viruses or internal pathogens without previous stimulation. [3][4][5][6] NK cell function is determined by signaling through several receptor families, including activating and inhibitory killer-cell Ig-like receptors (KIRs).…”

Human genes that limit AIDS

“…Certain HLA supertypes, grouped according to Bpocket contact residues of the antigenic peptide recognized by HLA class I alleles, show modest associations with HIV transmission and with circulating set-point HIV concentration (viral load) 68 . Alleles of the HLA-Bw4 grouping, which comprises 40% of HLA-B alleles that share a seven-amino acid motif, are associated with long-term nonprogressors, although the study reporting this was controversial 65,67 . HLA-Bw4 alleles serve as a ligand for certain natural killer cell receptors encoded by the killer immunoglobulin receptor (KIR) gene complex on chromosome 19 (ref.…”

“…Some provocative HLA associations involving functionally relevant HLA allele groupings with HIV infection and progression have also been reported 67,68 . Certain HLA supertypes, grouped according to Bpocket contact residues of the antigenic peptide recognized by HLA class I alleles, show modest associations with HIV transmission and with circulating set-point HIV concentration (viral load) 68 .…”

Immune responses during spontaneous control of HIV and AIDS: what is the hope for a cure?

“…The HLA-B alleles B*27 and B*57, which are commonly overrepresented in HICs [65][66][67], are members of the Bw4-80I group [68], suggesting that NK cells may contribute to establishing HIV control in these patients through direct cytolytic or non-cytolytic anti-HIV activities or by favouring the induction of an efficient CD8þ T cell response (see below) through optimal crosstalk with dendritic cells. Various reports suggest that NK cells from HICs have increased cytolytic and secretory potential [69][70][71], which may be associated with particular NK cell receptor profiles [69,71].…”