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Title: Characterisation of molecular mechanisms involved in nevirapine-induced hypersensitivity
Author: Cornejo Castro, Elena Maria
ISNI:       0000 0004 5364 1274
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2014
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The non-nucleoside reverse transcriptase inhibitor nevirapine (NVP) is widely used in the treatment of human immunodeficiency virus infection in many sub- Saharan countries. However, NVP-treated individuals have a 5% risk of developing hypersensitivity reactions (HSRs), ranging from maculopapular exanthema to life-threatening severe cutaneous eruptions and hepatotoxicity. A number of clinical (gender and CD4+ T cell count) as well as immunogenetic factors (MHC class I and class II alleles) have been associated with NVP hypersensitivity, but the predictive value is poor. Gene expression analyses provide an unbiased method for determining which immune-related mechanisms are involved in the pathogenesis of NVP hypersensitivity. mRNA microarray analysis demonstrated that expression of CD177, a neutrophil specific antigen, was significantly increased in our cohort of NVP-treated patients from Malawi (p ≤ 0.001), but also after in vitro treatment of NVP-hypersensitive patients from Liverpool (p < 0.05). Interestingly, CD177 protein expression did not increase in patient samples treated with NVP in vitro. A case-control study (n = 288) of NVP-hypersensitive and tolerant patients showed that none of the investigated CD177 polymorphisms were associated with NVP-induced HSRs. Of the clinical factors analysed, only CD4+ T cell count was significantly associated with NVP hypersensitivity (p < 0.001). The polymorphisms rs45441892 and rs10425385 in CD177 have previously been associated with an increased proportion of CD177-positive granulocytes. We confirmed these results in our NVP-naïve, healthy volunteer cohort (n = 35) for rs10425385, but not rs45441892. Previous reports have identified HLA-C*04:01 as a susceptibility marker for NVP-induced HSRs in patients from Malawi. Expression levels of miR-148a, a microRNA known to downregulate HLA-C expression, were analysed in serum samples from NVP-hypersensitive and tolerant individuals (n = 96). However, paradoxically, a statistically significant increase in miR-148a expression was found in NVP-hypersensitive patients at the time of reaction (p = 0.008). Additionally, the serum expression levels of 84 miRNAs were analysed in hypersensitive and tolerant patients treated with NVP (n = 24). Twenty-one miRNAs were differentially expressed in tolerant and hypersensitive samples. Of these miRNAs, miR-205 showed the highest increase in NVP-hypersensitive patients (p < 0.01). Besides HLA-C*04, several other HLA-alleles have been reported as risk factors for NVP hypersensitivity. A summary meta-analysis of published data indicated that four HLA-allelotypes (HLA-B*35, -B*58:01, -C*04, -DRB1*01) might be common risk factors of NVP-induced HSRs for different ethnicities. The results presented in this thesis highlight that various genetic, immunological and clinical factors may contribute to the pathogenesis of NVP hypersensitivity. Further understanding of the complex interactions may ultimately lead to the characterisation of true causative associations facilitating the precise prediction of hypersensitivity reactions to NVP.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: RM Therapeutics. Pharmacology