title: 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 b5reductase 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.
authors: Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, USA.
authors: Yat Yee
authors: YY
authors: Wong
authors: AIDS Vaccine Research Laboratory, Wisconsin National Primate Research Center, Madison, WI, USA.
authors: Eva G
authors: EG
authors: Rakasz
authors: Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, USA.
authors: David J
authors: DJ
authors: Gasper
authors: Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, USA; AIDS Vaccine Research Laboratory, Wisconsin National Primate Research Center, Madison, WI, USA.
authors: Thomas C
authors: TC
authors: Friedrich
authors: Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, USA. Electronic address: lauren.trepanier@wisc.edu.
authors: Lauren A
authors: LA
authors: Trepanier
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000009:adverse effects* / Q000097:blood; D000975:Antioxidants / Q000032:analysis; D001205:Ascorbic Acid / Q000097:blood; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D042966:Cytochrome-B(5) Reductase / Q000097:blood; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004342:Drug Hypersensitivity / Q000473:pathology* / Q000517:prevention & control; D005260:Female; D005978:Glutathione / Q000097:blood; D015658:HIV Infections / Q000188:drug therapy*; D007371:Interferon-gamma / Q000097:blood; D008070:Lipopolysaccharides / Q000097:blood; D008198:Lymph Nodes / Q000166:cytology / Q000187:drug effects; D008253:Macaca mulatta; D008297:Male; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000009:adverse effects* / Q000097:blood
chemical_list: D000890:Anti-Infective Agents; D000975:Antioxidants; D008070:Lipopolysaccharides; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D007371:Interferon-gamma; D042966:Cytochrome-B(5) Reductase; D005978:Glutathione; D001205:Ascorbic Acid
keywords: Hypersensitivity; Idiosyncratic; SIV; Simian immunodeficiency virus; Sulfamethoxazole; Sulfonamide