RESUMO
HIV-infected patients show a markedly increased risk of delayed hypersensitivity (HS) reactions to potentiated sulfonamide antibiotics (trimethoprim/sulfamethoxazole or TMP/SMX). Some studies have suggested altered SMX biotransformation in HIV infection, but hepatic biotransformation pathways have not been evaluated directly. Systemic lupus erythematosus (SLE) is another chronic inflammatory disease with a higher incidence of sulfonamide HS, but it is unclear whether retroviral infection and SLE share risk factors for drug HS. We hypothesized that retroviral infection would lead to dysregulation of hepatic pathways of SMX biotransformation, as well as pathway alterations in common with SLE that could contribute to drug HS risk. We characterized hepatic expression profiles and enzymatic activities in an SIV-infected macaque model of retroviral infection, and found no evidence for dysregulation of sulfonamide drug biotransformation pathways. Specifically, NAT1,NAT2,CYP2C8,CYP2C9,CYB5R3,MARC1/2, and glutathione-related genes (GCLC,GCLM,GSS,GSTM1, and GSTP1) were not differentially expressed in drug naïve SIVmac239-infected male macaques compared to age-matched controls, and activities for SMX N-acetylation and SMX hydroxylamine reduction were not different. However, multiple genes that are reportedly over-expressed in SLE patients were also up-regulated in retroviral infection, to include enhanced immunoproteasomal processing and presentation of antigens as well as up-regulation of gene clusters that may be permissive to autoimmunity. These findings support the hypothesis that pathways downstream from drug biotransformation may be primarily important in drug HS risk in HIV infection.
RESUMO
BACKGROUND: Sulfonamide hypersensitivity has a high incidence in HIV infection and correlates with low CD4+ counts, but the mechanisms are not understood. The aims of this study were to determine whether trimethoprim/sulfamethoxazole (TMP/SMX) led to SMX adduct formation, immunogenicity, or signs of drug hypersensitivity in SIV-infected rhesus macaques, and whether differences in antioxidants, pro-inflammatory mediators, or SMX disposition were predictive of drug immunogenicity. METHODS: Nine macaques chronically infected with SIVmac239 and 7 non-infected controls were studied. Baseline blood ascorbate, glutathione, IFN-γ, LPS, sCD14, and cytochrome b5 reductase measurements were obtained, macaques were dosed with TMP/SMX (120mg/kg/day p.o. for 14days), and SMX metabolites, lymph node drug adducts, drug-responsive T cells, and anti-SMX antibodies were measured. RESULTS: Four of 9 of SIV-positive (44%), and 3 of 7 SIV negative (43%) macaques had drug-responsive T cells or antibodies to SMX. Two macaques developed facial or truncal rash; these animals had the highest levels of lymph node drug adducts. Antioxidants, pro-inflammatory mediators, and SMX metabolites were not predictive of drug immunogenicity; however, the Mamu DRB1*0401/0406/0411 genotype was significantly over-represented in immune responders. CONCLUSIONS: Unlike other animal models, macaques develop an immune response, and possible rash, in response to therapeutic dosages of TMP/SMX. Studying more animals with CD4+ counts <200cells/µl, along with moderately restricted ascorbate intake to match deficiencies seen in humans, may better model the risk of SMX hypersensitivity in HIV-infection. In addition, the role of Mamu-DRB1 genotype in modeling drug hypersensitivity in retroviral infection deserves further study.
