Tissue-specific associations between mitochondrial DNA levels and current treatment status in HIV-infected individuals.
BACKGROUND
Tissue mitochondrial DNA (mtDNA) levels have been proposed as a marker of nucleoside analouge reverse transcriptase inhibitor (NRTI) toxicity. However, clinical studies have yielded conflicting data regarding possible associations with mtDNA levels. This study examined mtDNA levels in matched samples of peripheral blood mononuclear cells (PBMCs) and subcutaneous fat from a large Australian cohort to examine treatment, clinical, and demographic associations with mtDNA depletion.


METHODS
mtDNA was quantified by real-time polymerase chain reaction. Results were compared across patient treatment and demographic details using linear mixed models.


RESULTS
One hundred sixty-three PBMCs and 161 fat samples were available from 61 individuals. Current NRTI exposure was the major determinant of mtDNA levels. Both ddI (didanosine) and d4T (stavudine) exposures were associated with mtDNA depletion in fat (P < or = 0.0001 vs. those not on NRTIs). DdI exposure (P = 0.003), but not d4T exposure (P = 0.5), was associated with mtDNA depletion in PBMCs. No association between patient demographics or time on current therapy and mtDNA was observed.


CONCLUSIONS
Current NRTI exposure is the major determinant of tissue mtDNA, but the precise determinants are tissue specific. Both ddI and d4T exposure are associated with fat mtDNA depletion, whereas ddI exposure was the only observed association with mtDNA depletion in PBMCs.
Cherry
Catherine L
CL
Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, Australia. kcherry@burnet.edu.au
Nolan
David
D
James
Ian R
IR
McKinnon
Elizabeth J
EJ
Mallal
Simon A
SA
Gahan
Michelle E
ME
Lal
Luxshimi
L
McArthur
Justin C
JC
Wesselingh
Steven L
SL
D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D050151:Subcutaneous Fat / Q000378:metabolism
D019380:Anti-HIV Agents; D004272:DNA, Mitochondrial; D018894:Reverse Transcriptase Inhibitors