HIV Protective KIR3DL1/S1-HLA-B Genotypes Influence NK Cell-Mediated Inhibition of HIV Replication in Autologous CD4 Targets

Carriage of the genetic combination encoding a high expression inhibitory Killer Immunoglobulin-like Receptor (KIR)3DL1 with its ligand, HLA-B*57 (*h/*y+B*57) is associated with slower time to AIDS and better HIV viral load control than being a Bw6 homozygote (Bw6hmz). Natural Killer (NK) cells from *h/*y+B*57 carriers receive potent educational signals through HLA-B*57 KIR3DL1 ligation leading to high functional potential. NK cells from Bw6hmz are not educated through KIR3DL1 because Bw6 antigens do not interact with this inhibitory receptor. To better understand the impact of KIR/HLA combinations on NK cell mediated anti-viral activity we measured NK cell mediated inhibition of HIV replication in autologous infected CD4 (iCD4) cells by assessing the frequency of p24 positive CD4 targets and supernatant levels of HIV p24 longitudinally in the presence versus absence of NK cells. Forty-seven HIV uninfected subjects were studied, including carriers of *h/*y+B*57, a low expression KIR3DL1 genotype with HLA-B*57 termed *l/*x+B*57, a genotype designated 3DS1+*80I and Bw6hmz. NK cells from *h/*y+B*57 carriers, like those from 3DS1+*80I subjects, inhibited HIV replication in autologous iCD4 cells better than those from Bw6hmz and *l/*x+B*57 carriers. Cell contact between NK and iCD4 cells activated NK cells to inhibit viral replication in a non-contact dependent fashion through secretion of CC-chemokines. iCD4 stimulated NK cells from *h/*y+B*57 and 3DS1+*80I carriers produced higher levels of CC-chemokines than those from Bw6hmz or *l/*x+B*57 carriers. Higher levels of CC-chemokines were produced by KIR3DL1(+) than KIR3DL1(-) NK cells. We conclude that NK-mediated inhibition of viral replication in autologous iCD4 cells is partially due to a block at the level of HIV entry into new targets by secreted CC-chemokines. Author Summary Natural Killer (NK) cells function in anti-tumor and anti-viral defenses, including those directed against HIV. HIV infected cells can activate NK cells, which, once activated, inhibit HIV replication in infected targets. NK cell activation levels depend on the interaction of cell surface receptors on NK cells with the molecules (or ligands) they recognize on neighboring target cells. One receptor-ligand combination has been identified to have a strong effect on slowing time to AIDS, HIV viral load control and NK cell activation potential. We compared anti-HIV NK cell responses in individuals with this NK receptor-ligand combination to those from subjects having NK receptor-ligand combinations associated a neutral effect on time to AIDS. NK cells inhibited HIV replication in autologous infected cells more potently when they came from individuals with NK receptor-ligand (KIR/HLA) gene combinations associated with slow versus typical time to AIDS. Inhibition of HIV replication was due to secretion of factors (chemokines) that bind and block the co-receptor HIV uses to enter susceptible target cells. NK cells from subjects with KIR/HLA combinations associated with potent NK cell anti-HIV activity secreted more chemokines than those from subjects with KIR/HLA combinations associated with weak anti-HIV NK cell activity.