Sequence-based genotyping of killer cell immunoglobulin-like receptors and their associations with HIV-1 resistance and disease progression.

摘要

An HIV-1 vaccine is desperately needed, and understanding the biological factors that contribute to protective responses against HIV-1 in a cohort of HIV-1 resistant sex workers from Nairobi, Kenya may provide new insight for vaccine design. HIV-1 resistance is thought to be multifaceted; therefore, a comprehensive understanding will be crucial. Killer cell immunoglobulin-like receptors (KIRs) on natural killer (NK) cells are ligands for human leukocyte antigen (HLA) antigens, which are major factors in the susceptibility to HIV-1. Based on their ability to mediate NK activity, and their associations with other viral and autoimmune diseases, we hypothesized that KIR2DL2/2DL3/HLA-C genotypes play a role in HIV-1 resistance in the Pumwani cohort.;A novel sequence-based method was successfully developed and used to type KIR2DL2/2DL3 genes and allele groups for 957 women in the Pumwani cohort. Eight new allele groups were also identified. We found that KIR2DL3/HLA-C1 homozygosity, which is thought to mediate weaker inhibition, was associated with HIV-1 resistance, possibly due to higher NK activity in the innate response to HIV-1. KIR2DL2 is strongly inhibitory, and can bind both HLA-C1 and HLA-C2. Women who were homozygous for KIR2DL2 had slower progression to AIDS, possibly due to lowering immune activation, which is known to be detrimental in the spread of HIV-1 during chronic infection. A novel variant of KIR2DL2 was associated with faster disease progression, possibly due to a change in the amino acid that that reduces its binding affinity for HLA-C2. The association of KIRs with HIV-1 emphasizes the importance of NK-mediated cytotoxicity in HIV-1 resistance, but also its potential detriment in disease progression.