Mechanisms of risk for sulfonamide hypersensitivity Hypersensitivity (HS) to potentiated sulfonamide antibiotics is one of the most common idiosyncratic adverse drug reactions, affecting about 3% of the general population, and up to 50-60% of HIV-infected patients. Sulfamethoxazole (SMX), in combination with trimethoprim (TMP), can lead to fever, skin rash and multi-organ toxicity, and is the leading cause of life-threatening bullous skin eruptions in human patients. A better understanding of the mechanisms of risk in both immunocompetent and HIV-infected patients is needed to better predict and prevent these reactions. This is particularly important in light of the widespread use of these antimicrobials fo infection prophylaxis in immunocompromised patients, as well as their renewed use for methicillin-resistant Staph. aureus infections. Specific aim 1a will focus on genetic risk of sulfonamide HS in immunocompetent patients, which appears to be familial, using a two-stage GWAS design with tolerant patients as controls. Specific aim 1b will focus on the observation that peripheral blood mononuclear leukocytes (PBMCs) from HS patients are more susceptible to toxicity from sulfonamide metabolites compared to drug tolerant patients. Understanding the mechanism(s) for this surrogate marker may provide insight into the mechanisms of risk for systemic drug hypersensitivity. This subaim will identify differentially expressed transcripts in PBMCs from carefully phenotyped sulfonamide HS versus tolerant patients, and confirm the mechanistic significance of candidate transcripts by determining the effects of knock-down or over-expression on the cytotoxicity from sulfonamide metabolites in lymphoid cells. Together, these studies will characterize genetic risk for sulfonamide HS patients on both the genomic and transcriptional levels. In Aim 2, we will explore acquired risk factors for sulfonamide HS in HIV infection, using an SIV infection model in rhesus macaques. Baseline data, to include antioxidant and cytokine profiles, in vitro cytotoxicity assays, and liver and leukocyte expression profiles, will be obtained, followed by oral administration of a therapeutic dosage of TMP-SMX. Primary outcomes will include development of serum drug adducts, drug specific T cells, and toxicologic signs consistent with sulfonamide HS, along with baseline predictors for these outcomes. The goal of these aims is to better understand the genetic and acquired risk factors for sulfonamide drug hypersensitivity, so that better predictive and preventative measures can be developed. The ultimate goal is to improve the safety of this inexpensive antimicrobial for both the general population and for HIV-infected patients. PUBLIC HEALTH RELEVANCE: The potentiated sulfonamide antimicrobial, sulfamethoxazole with trimethoprim, is one of the most common causes of drug hypersensitivity reactions, to include fever and pruritic skin rash. Idiosyncratic sulfonamide drug hypersensitivity reactions are difficult to predict, but appear to have a genetic predisposition in the general population, with a acquired risk that is much higher in HIV-infected patients. The overall goals of the proposed studies are to identify genetic risk factors for sulfonamide hypersensitivity in the general population, and to characterize the reasons for the high incidence of these reactions in HIV-infected patients, so that we can develop better ways to predict and prevent these adverse drug reactions. !