HLA and NK receptor genes in HIV progression.

NK cell receptors and HLA molecules are intimately involved in the immune response against viral infections. The killer immunoglobulin-like receptors (KIRs) on NK cells regulate responses via the recognition of particular HLA class I products on the surface of infected cells. At the genomic level, both genetic systems are highly polymorphic and have recognised haplotypes, which adds complexity to their interaction. Previously, we and others have shown the association of HLA class I with HIV progression. More recently, the Carrington group observed a synergistic effect involving the activating KIR3DS1 allele and HLA-B Bw4-80Ile on the progression to depletion of CD4+ T cells, suggestive of an interactive model in the immune response to HIV infection. To further investigate the relationship between the two genetic systems, we examined changes in viral load in 249 pre-treatment patients from the Western Australia HIV cohort. Genetic variants known to affect HIV progression were associated with changes in HIV-1 viral load. However, we could not show a significant association with KIR3DS1 nor the epistatic effect with Bw4-80Ile. When we examined only those patients with known seroconversion dates, we found that the KIR3DS1 allele was associated with rapid progression to depletion of CD4+ T cells (p=0.01). We did not have sufficient statistical power to determine the KIR3DS1 and Bw4-80Ile relationship, but suggest that other KIR genes may be involved. We suggest that further analyses of haplotypes in both genetic systems is needed to understand their complex interactions in driving NK cell responses to HIV and disease