Subcutaneous adipocyte apoptosis in HIV-1 protease inhibitor-associated lipodystrophy

Background: Inhibitors of HIV-1 protease produce a rapid decrease in plasma HIV-1 RNA, with concomitant immune reconstitution. However, severe metabol ic side effects together with a previously unseen form of lipodystrophy hav e been associated with long-term use of protease-inhibitor therapy. The pat hogenic mechanisms underlying HIV-1 protease inhibitor-associated lipodystr ophy are still largely unknown. Methods: Fourteen HIV-infected patients with HIV-1 protease inhibitor-assoc iated lipodystrophy had a biopsy of subcutaneous fat performed in the anter o-lateral aspect of the right leg. The samples were submitted for standard pathologic study together with a careful search for adipocyte apoptosis. Ap optosis was assessed by the terminal deoxynucleotidyl transferase dUTP-digo xigenin nick end labelling (TUNEL) method, using the ApopTag kit (Oncor, Ga ithersburg, Maryland, USA). The procedure was performed between three and f ive times for each sample. Appropriate positive and negative controls were used. Controls which were subcutaneous fat biopsies from patients with untr eated melanoma were also examined for the presence of apoptosis. Results: Fourteen HIV-infected patients with a mean exposure to HIV-1 prote ase inhibitors of 12.6 +/- 3.7 months (range: 6-21 months), developed the c haracteristic features of HIV-1 protease inhibitor-associated lipodystrophy . All but one patient had an abnormal waist:hip ratio, and they all exhibit ed an abnormal serum lipid profile. Pathologically, subcutaneous fat atroph y was a constant feature, along with focal lipogranuloma formation and vasc ular proliferation. One of the eleven assessable biopsy samples was negativ e for the presence of apoptosis, six showed focally positive apoptotic cell s, and the remaining four biopsies demonstrated moderate positivity. Apopto tic changes were also detected in endothelial cells. Apoptotic changes were more pronounced in patients with higher increases in CD4 and CD8 counts, a nd in those with a greater decay in plasma viral load. Conclusions: Subcutaneous adipocyte apoptosis occurs in lipoatrophic areas of patients with HIV-1 protease inhibitor-associated lipodystrophy. (C) 199 9 Lippincott Williams & Wilkins.