Gene expression and immunohistochemistry in adipose tissue of HIV type 1-infected patients with nucleoside analogue reverse-transcriptase inhibitor-associated lipoatrophy.
BACKGROUND
Long-term use of both zidovudine (AZT) and stavudine (d4T) is associated with lipoatrophy, but it occurs possibly through different mechanisms.


METHODS
Surgical biopsy specimens of subcutaneous adipose tissue were obtained from 18 human immunodeficiency virus type 1 (HIV-1)-infected lipoatrophic patients (the LA+ group) who were treated with either zidovudine (the AZT+LA+ group; n = 10) or stavudine (the d4T+LA+ group; n = 8) and from 10 nonlipoatrophic HIV-1-infected patients (the LA- group) who received antiretroviral therapy. Mitochondrial DNA (mtDNA) copy numbers, gene expression, and immunohistochemistry data were analyzed.


RESULTS
mtDNA copy numbers were significantly reduced in the LA+ group, compared with the LA- group, and in the d4T+LA+ group, compared with the AZT+LA+ group. The ratio of mtDNA-encoded cytochrome COX3 to nuclear DNA-encoded COX4 expression was significantly lower in the LA+ group than in the LA- group. Compared with the LA- group, the LA+ group had significantly lower expression of genes involved in adipogenesis (SREBP1c and CEBPB), lipid (fatty acid synthase), and glucose (GLUT4) metabolism. Expression of genes involved in mitochondrial biogenesis (PGC1B), apoptosis (FAS), inflammation (IL1B), oxidative stress (PCNA and SOD1), and lamin B was significantly higher in the LA+ group than in the LA- group. The d4T+LA+ group had significantly lower expression of genes involved in mitochondrial biogenesis (POLG1), energy metabolism (the COX3/COX4 ratio), adipogenesis (SREBP1c and CEBPA), perilipin, and hexokinase than did the AZT+LA+ group. There were 7-fold more macrophages in adipose tissue specimens obtained from patients in the LA+ group, compared with the LA- group.


CONCLUSIONS
Lipoatrophy is characterized by mtDNA depletion, inflammation, and signs of apoptosis. Changes were more profound in the d4T+LA+ group than in the AZT+LA+ group.
Sievers
M
M
Department of Rheumatology and Clinical Immunology, Medizinische Universitätsklinik, Freiburg, Germany.
Walker
U A
UA
Sevastianova
K
K
Setzer
B
B
Wågsäter
D
D
Eriksson
P
P
Yki-Järvinen
H
H
Sutinen
J
J
D017667:Adipocytes / Q000378:metabolism; D019380:Anti-HIV Agents / Q000009:adverse effects* / Q000627:therapeutic use; D000074002:DNA Polymerase gamma; D004272:DNA, Mitochondrial / Q000187:drug effects / Q000378:metabolism; D004259:DNA-Directed DNA Polymerase; D005260:Female; D020869:Gene Expression Profiling; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics; D039682:HIV-Associated Lipodystrophy Syndrome / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D019384:Nucleic Acid Synthesis Inhibitors; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D018119:Stavudine / Q000009:adverse effects* / Q000627:therapeutic use; D050507:Subcutaneous Fat, Abdominal / Q000378:metabolism / Q000473:pathology; D015215:Zidovudine / Q000009:adverse effects* / Q000627:therapeutic use
D019380:Anti-HIV Agents; D004272:DNA, Mitochondrial; D019384:Nucleic Acid Synthesis Inhibitors; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine; D018119:Stavudine; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human; D005947:Glucose