In vitro models as surrogates of in vivo antiretroviral efficacy in central nervous system of HIV-1 infected subjects
File(s)
Author(s)
Mora Peris, Borja
Type
Thesis
Abstract
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.
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.
Version
Open Access
Date Issued
2016-08
Date Awarded
2017-03
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Winston, Alan
Herrera, Carolina
Shattock, Robin
Sponsor
Imperial College London
Publisher Department
Department of Medicine
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)