Developing safer HIV drugs: elucidating the mechanistic pathway of Tenofovir-induced cytotoxicity via mitochondrial dysfunction

Mellor, Claire Developing safer HIV drugs: elucidating the mechanistic pathway of Tenofovir-induced cytotoxicity via mitochondrial dysfunction. Doctor of Philosophy thesis, University of Liverpool.

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Abstract

Human immune deficiency virus (HIV) currently affects around 34 million people worldwide, but due to recent advancements in antiretroviral treatments the morbidity and mortality of HIV has greatly improved (UNIAIDS, 2009). Tenofovir (TFV) is a nucleoside reverse transcriptase inhibitor (NRTI) that is currently widely used in most HIV regimens due to its favourable pharmacokinetic and pharmacodynamic properties, which allows for once daily dose (Gallent et al., 2004). TFV is used to treat HIV in both treatment experienced and treatment naive patients; it is also used as a treatment for hepatitis B and has recently been approved for use as a pre-exposure prophylaxis treatment. The preclinical trials for TFV showed that it had a good safety profile, however there has been an increasing number of patients presenting with TFV induced renal damage specifically proximal tubule dysfunction (Cooper et al., 2010). It was hypothesised that TFV was inducing this tubule damage via mitochondrial dysfunction, as this has been widely reported as an adverse reaction associated with NRTI’s (Kontorinis et al., 2003). Within these studies in vitro cell models were modified via culturing them in galactose media in order to probe for mitotoxins (Marroquin et al., 2007). The cytotoxicity and mechanisms of cell death induced via TFV were elucidated within these modified cell lines. Work presented has shown that TFV causes delayed mitochondrial cytotoxicity, which causes a cell cycle arrest within the G2/M phase leading to an accumulation of cell within the S phase. It was shown that the cell cycle arrest is likely due to the inhibition of mitochondrial polymerase γ leading to decreased mitochondrial DNA and ultimately cell death firstly via apoptosis (caused by release of caspase 3/ 7), and then necrosis when cellular ATP levels become too low to sustain apoptosis. Work presented also showed that autophagy induced by TFV, may play a protective role within cells at lower time period. A study within this thesis using patient urine samples was presented to look for a possible biomarker of TFV proximal tubule dysfunction. Kidney injury molecule-1 (KIM-1) was selected as previous studies have shown that it is specific to proximal tubule cells (Ichimura et al., 2008). Results demonstrated that TFV did not significantly alter the KIM-1 / creatinine ratio within patient urine samples. However the data from this pilot study are novel and should be used for future research into the possible use of KIM-1 as a biomarker for TFV induced proximal tubule dysfunction. The biomarker work presented within this thesis should be carried forward to power a future study using a larger and adequate patient cohort. The work presented within this thesis has now opened doors for further study into this subject area especially with regards to the study of KIM-1 as a biomarker, which is a pressing matter as TFV is now widely available for use as a PrEP treatment.

Item Type:	Thesis (Doctor of Philosophy)
Additional Information:	Date: 2014-04 (completed)
Subjects:	?? RM ??
Divisions:	Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User:	Symplectic Admin
Date Deposited:	08 Aug 2014 10:51
Last Modified:	16 Dec 2022 04:41
DOI:	10.17638/00017093
Supervisors:	Chadwick, Amy Liptrott, Neill Back, David Park, Kevin ORCID: 0000-0001-8384-824X
URI:	https://livrepository.liverpool.ac.uk/id/eprint/17093