Psoriasis Patients Are Enriched for Genetic Variants That Protect against HIV-1 Disease

Abstract

An important paradigm in evolutionary genetics is that of a delicate balance between genetic variants that favorably boost host control of infection but which may unfavorably increase susceptibility to autoimmune disease. Here, we investigated whether patients with psoriasis, a common immune-mediated disease of the skin, are enriched for genetic variants that limit the ability of HIV-1 virus to replicate after infection. We analyzed the HLA class I and class II alleles of 1,727 Caucasian psoriasis cases and 3,581 controls and found that psoriasis patients are significantly more likely than controls to have gene variants that are protective against HIV-1 disease. This includes several HLA class I alleles associated with HIV-1 control; amino acid residues at HLA-B positions 67, 70, and 97 that mediate HIV-1 peptide binding; and the deletion polymorphism rs67384697 associated with high surface expression of HLA-C. We also found that the compound genotype KIR3DS1 plus HLA-B Bw4-80I, which respectively encode a natural killer cell activating receptor and its putative ligand, significantly increased psoriasis susceptibility. This compound genotype has also been associated with delay of progression to AIDS. Together, our results suggest that genetic variants that contribute to anti-viral immunity may predispose to the development of psoriasis. Individuals with autoimmune disease generally demonstrate excessive immune system activation, leading to inflammation and damage of specific target organs. However, in some cases the detrimental effects of an overactive immune system might be counterbalanced by a beneficial effect in protecting against certain infections. In this study, we investigated whether patients with psoriasis, a common autoimmune disease of the skin, harbor genetic variants that are associated with an enhanced ability to limit replication of the HIV-1 virus. We profiled the HLA (human leukocyte antigen) immune genes located on chromosome 6 in 1,727 Caucasian psoriasis cases and 3,581 healthy controls and found that psoriasis patients are significantly more likely than controls to have gene variants that are protective against HIV-1 disease. We found that this enrichment for HIV-1 protective variants was unique to psoriasis and largely absent in patients with other autoimmune or inflammatory diseases such as rheumatoid arthritis, Crohn's disease, type 1 diabetes, type 2 diabetes, and coronary artery disease. Our results suggest the possibility that the excessive skin inflammation in psoriasis may be associated with activation of anti-viral immune pathways that were important to human ancestors who encountered viruses similar to HIV-1.