Tumour necrosis factor alpha in fat redistribution syndromes associated with combination antiretroviral therapy in HIV-1-infected patients: potential role in subcutaneous adipocyte apoptosis.
BACKGROUND
The pathogenesis of fat redistribution syndromes (FRS) observed in the setting of highly active antiretroviral therapy (HAART) for the treatment of HIV-1-infection remains elusive. A dysregulation of the tumour necrosis factor alpha (TNF-alpha) system occurs in HIV-infected patients with FRS.


METHODS
The study looked at both the in vivo and in vitro relationship between TNF-alpha and the degree of subcutaneous adipocyte apoptosis in 60 HIV-1-infected patients on HAART with FRS, another 60 HIV-1-infected patients on HAART without FRS and 60 uninfected control patients. Apoptosis was assessed by the terminal deoxynucleotidyl transferase dUTP (deoxyuridine 5'-triphosphate)-digoxigenin Nick End Labelling (TUNEL) method. Soluble receptors of TNF-alpha were determined by the sandwich enzyme immunoassay technique. The in vitro viability was assessed by staining with 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) and apoptosis by TUNEL.


RESULTS
HIV-1-infected patients with FRS had significantly higher degrees of subcutaneous adipocyte apoptosis than those without FRS (P = 0.0001) and uninfected controls (P < 0.0001). There was a statistically significant association between serum levels of soluble TNF-alpha receptors #1 and #2 and the degree of subcutaneous adipocyte apoptosis in patients with and without FRS (P < 0.0001 for both receptors). In vitro, the addition of TNF-alpha (10 ng mL(-1)) to an adipocyte culture embedded with indinavir, either alone or in clinically relevant combinations with stavudine (d4T) and lamivudine (3TC), significantly decreased adipocyte viability (P = 0.0001) and increased adipocyte apoptosis (P < 0.0001) with respect to that observed with the addition of antiretrovirals alone.


CONCLUSIONS
TNF-alpha plays a significant role in subcutaneous adipocyte apoptosis, which occurs in the setting of FRS in HIV-1-infected patients on highly active antiretroviral therapy.
Domingo
P
P
Department of Internal Medicine (Infectious Diseases Unit), Autonomous University of Barcelona, Barcelona, Spain. pere.domingo@uab.es
Vidal
F
F
Domingo
J C
JC
Veloso
S
S
Sambeat
M A
MA
Torres
F
F
Sirvent
J J
JJ
Vendrell
J
J
Matias-Guiu
X
X
Richart
C
C
D016475:3T3 Cells; D017667:Adipocytes / Q000473:pathology; D000328:Adult; D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active; D017209:Apoptosis; D016022:Case-Control Studies; D005260:Female; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy* / Q000276:immunology*; D015497:HIV-1; D006801:Humans; D020287:In Situ Nick-End Labeling; D019259:Lamivudine / Q000494:pharmacology; D008060:Lipodystrophy / Q000276:immunology* / Q000473:pathology / Q000821:virology; D008297:Male; D051379:Mice; D008875:Middle Aged; D011446:Prospective Studies; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000097:blood; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000097:blood; D013194:Staining and Labeling; D018119:Stavudine / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis*
D019380:Anti-HIV Agents; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D019259:Lamivudine; D018119:Stavudine