[P-01] The effect of antiretroviral therapy on genes involved with mitochondrial function

9th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV

19-21 July 2007, Sydney, Australia

THE EFFECT OF ANTIRETROVIRAL THERAPY ON GENES INVOLVED WITH MITOCHONDRIAL FUNCTION

Antiviral Therapy 2007; 12(Suppl. 2):L23 (abstract no. P-01)

M Boothby¹, JW Tomlinson², KC McGee³, S Das⁴, LL Gathercole², AL Harte³, P Higgins³, CM Kusminski³, PG McTernan³ and M Shahmanesh¹
¹University Hospital Birmingham, Birmingham, UK; ²University of Birmingham, Birmingham, UK; ³Warwick University, Warwick, UK; ⁴University Hospitals Coventry and Warwickshire, Coventry, UK

OBJECTIVES: To compare patterns of gene expression in the subcutaneous adipose tissue of HIV-positive subjects before and after 6 months of antiretroviral therapy with HIV-negative controls.

METHODS: Subcutaneous fat biopsies from the iliac crest were performed on 18 HIV-positive patients and 10 HIV- negative controls. Following total RNA extraction, gene expression was profiled using real-time PCR and quantified relative to an internal house-keeping gene (18S). Genes were involved in nuclear regulation of mitochondrial RNA or mitochondrial respiratory chain. HIV-positive patients were tested before, and 6 months after randomization to either zidovudine/lamivudine or tenofovir/ emtricitabine with efavirenz. Comparison between groups was by t-tests and Mann–Whitney test.

RESULTS: There were no differences in sex, ethnicity, BMI, whole body DEXA, and abdominal CT scans between groups. Mitochondrially encoded respiratory genes NADH dehydrogenase 4 (ND4), cytochrome b (CYT-B) and cytochrome c oxidase subunit III (COX3) were increased in HIV-naïve patients versus controls. ND4 expression further increased after treatment alongside expression of human citrate synthase (HCS, a key enzyme in TCA cycle), genes controlling transcription of mitochondrial RNA (NRF-1 and TFAM) and uncoupling protein 2 (UCP2), but not UCP1 and UCP3. However, CYTB and COX3 decreased after treatment. The reduction in expression of CYT-B (P<0.0001) and COX3 (P=0.003) was significant for zidovudine (0.6 and 1.0, respectively), but not tenofovir (1.5 and 1.6, respectively).


Table 1. Fold change in gene expression from HIV-negative controls (control =1) (Abstract P-01)

Gene	Naïve HIV	6 month	P-value

PCG1α	1.41	1.59	0.04*
NRF-1	1.2	1.53	0.05†, 0.01*
TFAM	1.07	1.65	0.009*, 0.0001‡
ND4	1.19	8.1	0.008†, 0.00006*
CYT-B	2.08	0.97	0.0002†, 0.0004*
COX3	2.0	1.32	0.001†, 0.003*
UCP2	0.89	1.3	0.03*
HCS	1.14	2.03	0.01*

*naïve versus 6 month; †naïve versus control; ‡control versus 6 month.

CONCLUSION: Expression of mitochondrial respiratory genes are increased with HIV infection compared to controls. These fall to control levels after 6 months use of zidovudine but not tenofovir. Increased mitochondrial respiratory chain activity in HIV infection may contribute to the abnormalities in adipocyte metabolism in HIV.

Download PDF of this abstract.

2007-07-24
P-01

Copyright © 2007 - International Medical Press Ltd. Reproduction of this abstract (other than one copy for personal reference) must be cleared through the Medical Editor, International Medical Press, 36 St Mary-at-Hill, London EC3R 8DU, United Kingdom.