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Title: In vitro models as surrogates of in vivo antiretroviral efficacy in central nervous system of HIV-1 infected subjects
Author: Mora Peris, Borja
ISNI:       0000 0004 7228 8656
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2016
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HIV-associated cognitive disorders persist despite combination antiretroviral therapy (cART). The pathogenesis of HIV-associated cognitive disorders has been attributed to factors including the presence of co-morbidities, neuro-inflammation, central nervous system (CNS) antiretroviral toxicity and sub-optimal CNS penetration of antiretroviral drugs. With regards to cART activity in the CNS compartment, attempts have been made to develop pharmacokinetic scoring systems in order to assess CNS antiretroviral efficacy. However, the evidence regarding their clinical validity is non-conclusive. I aimed to establish a novel scoring system to assess antiretroviral efficacy in CNS models. Neurologic cell line-based infectivity assays were developed using brain-derived HIV-1 isolates to calculate CNS anti-retroviral (CAR) scores. CSF samples were collected from HIV-positive neuro-asymptomatic patients receiving cART within clinical studies which also evaluated cerebral parameters including CSF pharmacokinetic parameters, CSF soluble biomarkers, cerebral metabolites measured via magnetic resonance spectroscopy (MRS) and cognitive testing. I hypothesised that greater in vitro CSF CAR scores are associated with greater CSF concentrations of antiretroviral drugs and higher indices of cerebral function parameters. I identified significant differences between CSF CAR scores of patients on differing cART regimens alongside significant correlations between the CSF CAR scores and CSF antiretroviral concentrations of all third antiretroviral drugs in such regimens. Higher CSF CAR scores were associated with higher markers of neuronal integrity (MRS) in patients on a maraviroc containing cART regimen but with higher levels of neuronal toxicity biomarkers in an efavirenz containing regimen. These data highlight that antiretrovirals with known immunomodulatory or toxic effects may have such effects on the CNS. I did not observe any associations between CSF CAR scores and cognitive function. CSF CAR scores are a novel research tool able to discriminate the CNS effects of differing cART regimens and may have a future role in research programmes when utilised with other markers of CNS function.
Supervisor: Winston, Alan ; Herrera, Carolina ; Shattock, Robin Sponsor: Imperial College London
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral