Cytokine expression in the muscle of HIV-infected patients: evidence for interleukin-1 alpha accumulation in mitochondria of AZT fibers.

To evaluate the possible role of cytokines in human immunodeficiency virus (HIV)-associated muscular disorders, we performed immunocytochemistry for interleukin-1 alpha, -1 beta, and -6 and tumor necrosis factor-alpha on frozen muscle biopsy specimens from HIV-infected patients with various myopathies (HIV polymyositis in 5, HIV-wasting syndrome in 5, zidovudine myopathy in 10) and from seronegative individuals (normal muscle in 2, mitochondrial cytopathies in 10). The HIV-infected patients showed positive reactivities in vessels (interleukin-1) and in inflammatory cells (mainly interleukin-1 and tumor necrosis factor-alpha), including perivascular hemosiderin-laden macrophages in 5 patients. In zidovudine myopathy, a majority of AZT fibers (i.e., ragged-red fibers with marked myofibrillar changes) showed mild to marked expression of interleukin-1. Expression of interleukin-1 in the other mitochondrial myopathies was much weaker. Interleukin-1 beta messenger RNA was demonstrated in muscle fibers by in situ hybridization, implying that interleukin-1 was produced in muscle cells. Immunoelectron microscopy showed that interleukin-1 alpha was mainly bound to mitochondrial membranes in AZT fibers. Proinflammatory and destructive effects of the studied cytokines might be responsible for several myopathological changes observed in HIV-infected patients, including inflammation and hemosiderin deposits in muscle tissue, and prominent myofibrillar breakdown in AZT fibers.