Immunogenicity of trimethoprim/sulfamethoxazole in a macaque model of HIV infection

Abstract

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.

Keywords: Hypersensitivity; Idiosyncratic; SIV; Simian immunodeficiency virus; Sulfamethoxazole; Sulfonamide.

Figure 1

Biotransformation of sulfamethoxazole (SMX) with generation of reactive metabolites that lead to hapten formation, immunogenicity, and clincial signs of delayed sulfonamide hypersensitivity.

Figure 2

Surface drug (SMX; sulfamethoxazole) adducts detected in inguinal lymph node lymphocytes from SIV-infected macaques and non-infected controls, after dosing with TMP/SMX at 120 mg/kg/day per os for 14 days. Highlighted data points indicate outlier high adduct formation in 2 macaques that developed transient erythematous rashes during treatment.

Figure 3

Plasma ascorbate (AA; panel A) and erythrocyte reduced GSH (panel B) concentrations in SIV-infected macaques and non-infected controls prior to dosing with TMP/SMX.

Figure 4

Approximate peak plasma (panel A) and 24-hour urinary (panel B) concentrations of SMX-hydroxylamine (SMX-HA) in SIV-infected and control macaques administered TMP/SMX per os for 2 weeks.