Yat Yee Wong1, Eva G Rakasz2, David J Gasper3, Thomas C Friedrich4, Lauren A Trepanier5. 1. Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, USA. 2. AIDS Vaccine Research Laboratory, Wisconsin National Primate Research Center, Madison, WI, USA. 3. Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, USA. 4. 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. 5. Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, USA. Electronic address: lauren.trepanier@wisc.edu.
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.
BACKGROUND:Sulfonamidehypersensitivityhas 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 inSIV-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 SMXhypersensitivity inHIV-infection. In addition, the role of Mamu-DRB1 genotype in modeling drug hypersensitivity inretroviral infection deserves further study.
Authors: Natalie L Wilson; David E Vance; Linda D Moneyham; James L Raper; Michael J Mugavero; Sonya L Heath; Mirjam-Colette Kempf Journal: J Assoc Nurses AIDS Care Date: 2014-07-22 Impact factor: 1.354
Authors: Netanya G Sandler; Handan Wand; Annelys Roque; Matthew Law; Martha C Nason; Daniel E Nixon; Court Pedersen; Kiat Ruxrungtham; Sharon R Lewin; Sean Emery; James D Neaton; Jason M Brenchley; Steven G Deeks; Irini Sereti; Daniel C Douek Journal: J Infect Dis Date: 2011-01-20 Impact factor: 5.226