Background:  Killer cell immunoglobulin receptors (KIR) are regulatory molecules that control the cytolytic activity of natural killer (NK) cells. NK cells are components of the innate immune system’s early response to viral agents, functioning to produce cytokines or to destroy infected cells. In association with their specific major histocompatibility complex (MHC) ligands, inhibitory KIR molecules protect normal cells from being destroyed by down-regulating NK cytotoxicity. Inhibitory KIR responses are dominant over stimulatory ones, which act to promote NK cell-mediated cytolysis. Virally infected cells with down-regulated class I may also result in cell destruction. KIR loci are highly polymorphic and evolved rapidly, presumably due to selective pressures from pathogens.

Methods:  Here we present data from analysis of 14 KIR loci and MHC class I (A, B, C) alleles on a subset of the Chicago MACS patients, including 80 high-risk non-infected controls and 83 infected patients with known or estimated viral set points. The KIR and HLA loci were typed by PCR using sequence-specific probes. The KIR-HLA data were analyzed for association with transmission status (infected vs uninfected) and rate of disease progression, based on viral load and CD4⁺ counts.

Results:  A significant protective association with HIV transmission and 2DL1*004 (inhibitory) in absence of its cognate MHC ligand (K80 alleles) was observed, as was a similar protective effect with 3DS1 (activating) and absence of Bw4, a putative (but not proven) ligand. A reduction in the rate of disease progression was also observed in patients with these KIR-MHC conditions, particularly if 2 copies of the KIR genes were present. Our data suggest that, if the common 2DL1*004 variant is present without its MHC ligand, the inhibitory effect is abolished, increasing the probability of a cytolytic KIR-NK response. We further find no correlation between the presence of 2DL1*004 and the presence of 3DS1, indicating that the effects we observe for each of these KIR genes are independent.

Conclusions:  Previous analyses also demonstrated a protective effect of 3DS1 in disease progression with no associated role for Bw4, contrary to another study showing an epistatic association with 3DS1 and Bw4-80Ile. Our data indicate that multiple KIR genes may influence HIV infection status and disease outcome.

Keywords: Killer Immunoglobulin Recpetors (KIR); Natural Killer Cells; MHC