Genetic and cytometric analyses of subcutaneous adipose tissue in patients with hemophilia and HIV-associated lipodystrophy

• Published in: AIDS research and therapy Vol. 19; no. 1; pp. 14 - 10
• Main Authors: Mashiko, Takanobu, Tsukada, Kunihisa, Takada, Hitomi, Wu, Szu-Hsien, Kanayama, Koji, Asahi, Rintaro, Mori, Masanori, Kurisaki, Akira, Oka, Shinichi, Yoshimura, Kotaro
• Format: Journal Article
• Language: English
• Published: London BioMed Central 04.03.2022; BioMed Central Ltd; BMC
• Subjects: Adipose tissues; Adipose-derived stem cell; Anti-HIV Agents - therapeutic use; Complications and side effects; DNA, Mitochondrial - analysis; DNA, Mitochondrial - metabolism; DNA, Mitochondrial - therapeutic use; Gene analysis; Genetic aspects; Health aspects; Hemophilia; Hemophilia A - complications; Hemophilia A - drug therapy; HIV infection; HIV Infections - complications; HIV Infections - drug therapy; HIV Infections - pathology; HIV-associated lipodystrophy; HIV-Associated Lipodystrophy Syndrome - genetics; Human immunodeficiency virus; Humans; Infectious Diseases; Lipoatrophy; Lipodystrophy; Lipodystrophy - chemically induced; Lipodystrophy - complications; Lipodystrophy - genetics; Macrophage; Medicine; Medicine & Public Health; Risk factors; Subcutaneous Fat - chemistry; Subcutaneous Fat - metabolism; Subcutaneous Fat - pathology; Virology; Japan; HIV-associated lipodystrophy; Human immunodeficiency virus; Adipose-derived stem cell; Lipoatrophy; Gene analysis; Macrophage
• ISSN: 1742-6405; 1742-6405
• DOI: 10.1186/s12981-022-00432-9

Background The authors recently performed plastic surgeries for a small number of patients with hemophilia, HIV infection, and morphologic evidence of lipodystrophy. Because the pathophysiological mechanism of HIV-associated lipodystrophy remains to be elucidated, we analyzed subcutaneous adipose tissues from the patients. Methods All six patients had previously been treated with older nucleoside analogue reverse-transcriptase inhibitors (NRTIs; stavudine, didanosine or zidovudine). Abdominal and inguinal subcutaneous fat samples were obtained from the HIV+ patients with hemophilia and HIV− healthy volunteers (n = 6 per group), and analyzed via DNA microarray, real-time PCR, flow cytometry and immunohistochemistry. Results The time from initial NRTI treatment to collecting samples were 21.7 years in average. Cytometric analysis revealed infiltration of inflammatory M1 macrophages into HIV-infected adipose tissue and depletion of adipose-derived stem cells, possibly due to exhaustion following sustained adipocyte death. Genetic analysis revealed that adipose tissue from HIV+ group had increased immune activation, mitochondrial toxicity, chronic inflammation, progressive fibrosis and adipocyte dysfunction (e.g. insulin resistance, inhibited adipocyte differentiation and accelerated apoptosis). Of note, both triglyceride synthesis and lipolysis were inhibited in adipose tissue from patients with HIV. Conclusions Our findings provide important insights into the pathogenesis of HIV-associated lipodystrophy, suggesting that fat redistribution may critically depend on adipocytes’ sensitivity to drug-induced mitochondrial toxicity, which may lead either to atrophy or metabolic complications.