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

Immunogenicity of trimethoprim/sulfamethoxazole in a macaque model of HIV infection.
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Wong YY, Rakasz EG, Gasper DJ, Friedrich TC, Trepanier LA,


Wong YY, Rakasz EG, Gasper DJ, Friedrich TC, Trepanier LA, (click to view)

Wong YY, Rakasz EG, Gasper DJ, Friedrich TC, Trepanier LA,

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Toxicology 2016 8 23() pii 10.1016/j.tox.2016.08.010

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 14 days), 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<200 cells/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.

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