46-OR

Abstract

Aim Natural killer (NK) cells express a diverse repertoire of inhibitory and activating receptors that are regulated to defend against viral infection while ensuring self-tolerance. The major genes underlying these responses are the NK inhibitory and stimulatory KIR, and HLA class I and II. Here, we investigate the role of these genes in HIV infection and progression of HIV disease in the Chicago MACS cohort. Methods Men enrolled in the Chicago component of the Multicenter AIDS Cohort Study (MACS) who were at risk for (N = 499) or infected with (N = 602) HIV were genotyped for HLA alleles and KIR loci, and categorized by haplotypes and ligand pairings. For analysis of transmission, the marker frequency among HIV+ versus exposed but HIV- men was compared. For disease progression, we analyzed marker association with viral set point and with rate of CD4+ T cell decline. Results Analysis of HIV progression revealed a variety of HLA-B alleles, particularly B*57:01, associated with HIV viral load. CD4+T cell count was diminished in patients with A ∗24:02 (p = 0.009) and B ∗44:02 (p = 0.004). In absence of Bw4, KIR3DL1+ KIR3DS1+ patients had modest increase in viral load. Analysis of HIV infection status revealed significant protection with KIR2DL2 - KIR2DL3 + and HLA C 1/ C 1 compared with C 1/ C 2 or C 2/ C 2 ( p = 0.0006, q = 0.1198; OR = 0.506), and with C 1/ C 2 ( p = 0.0034, q = 0.159; OR = 0.548) or C 2/ C 2 ( p = 0.0016, q = 0.159; OR = 0.363). We interpret the C1/C1 association as reflecting the absence of the C2 ligand. The KIR2DS2 - and C1/C1 versus C1/C2 or C2/C2 gave similar result, reflecting the effect of Cen A/A in the absence of the C2 ligand. We propose that the strongly inhibitory KIR2DL1 is not triggered in absence of its C2 ligand and, thus, the NK activation and resistance to HIV infection is enhanced. Conclusions These observations suggest that KIR may play a greater role in HIV infection while an HLA antigenic response may play a greater role in controlling the progression of HIV infection.