Immunogenicity of Trimethoprim/sulfamethoxazole in a Macaque Model of HIV Infection

Overview

Journal Toxicology

Publisher Elsevier

Specialty Toxicology

Date 2016 Aug 28

PMID 27565715

Citations 3

Authors

Yat Yee Wong

Eva G Rakasz

David J Gasper

Thomas C Friedrich

Lauren A Trepanier

Affiliations

Soon will be listed here.

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 b 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.

Citing Articles

Antibiotic prophylaxis in immunosuppressed patients - Missed opportunities from trimethoprim-sulfamethoxazole allergy label.

Lee W, Lam L, Bacchi S, Jiang M, Inglis J, Smith W World Allergy Organ J. 2024; 17(1):100856.

PMID: 38235260 PMC: 10793173. DOI: 10.1016/j.waojou.2023.100856.

Drug hypersensitivity in HIV infection.

Peter J, Choshi P, Lehloenya R Curr Opin Allergy Clin Immunol. 2019; 19(4):272-282.

PMID: 31145192 PMC: 7236403. DOI: 10.1097/ACI.0000000000000545.

Hepatic expression profiles in retroviral infection: relevance to drug hypersensitivity risk.

Wong Y, Johnson B, Friedrich T, Trepanier L Pharmacol Res Perspect. 2017; 5(3):e00312.

PMID: 28603631 PMC: 5464341. DOI: 10.1002/prp2.312.

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