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Introduction of highly active antiretroviral therapy (HAART) has dramatically modified the natural history of HIV disease, but lengthening the survival of HIV-infected individuals has been associated with an increasing prevalence of iatrogenic conditions. Muscular complications of HIV infection are classified as follows: (1) HIV-associated myopathies and related conditions including polymyositis, inclusion-body myositis, nemaline myopathy, diffuse infiltrative lymphocytosis syndrome (DILS), HIV-wasting syndrome, vasculitis, myasthenic syndromes, and chronic fatigue; (2) iatrogenic conditions including mitochondrial myopathies, HIV-associated lipodystrophy syndrome, and immune restoration syndrome; (3) opportunistic infections and tumor infiltrations of skeletal muscle; and (4) rhabdomyolysis. These features are described in the present review.

Macrophagic myofasciitis is a condition first reported in 1998, which cause remained obscure until 2001. Over 200 definite cases have been identified in France, and isolated cases have been recorded in other countries. The condition manifests by diffuse myalgias and chronic fatigue, forming a syndrome that meets both Center for Disease Control and Oxford criteria for the so-called chronic fatigue syndrome in about half of patients. One third of patients develop an autoimmune disease, such as multiple sclerosis. Even in the absence of overt autoimmune disease they commonly show subtle signs of chronic immune stimulation, and most of them are of the HLADRB1*01 group, a phenotype at risk to develop polymyalgia rheumatica and rheumatoid arthritis. Macrophagic myofasciitis is characterized by a stereotyped and immunologically active lesion at deltoid muscle biopsy. Electron microscopy, microanalytical studies, experimental procedures, and an epidemiological study recently demonstrated that the lesion is due to persistence for years at site of injection of an aluminum adjuvant used in vaccines against hepatitis B virus, hepatitis A virus, and tetanus toxoid. Aluminum hydroxide is known to potently stimulate the immune system and to shift immune responses towards a Th-2 profile. It is plausible that persistent systemic immune activation that fails to switch off represents the pathophysiologic basis of chronic fatigue syndrome associated with macrophagic myofasciitis, similarly to what happens in patients with post-infectious chronic fatigue and possibly idiopathic chronic fatigue syndrome. Therefore, the WHO recommended an epidemiological survey, currently conducted by the French agency AFSSAPS, aimed at substantiating the possible link between the focal macrophagic myofasciitis lesion (or previous immunization with aluminium-containing vaccines) and systemic symptoms. Interestingly, special emphasis has been put on Th-2 biased immune responses as a possible explanation of chronic fatigue and associated manifestations known as the Gulf war syndrome. Results concerning macrophagic myofasciitis may well open new avenues for etiologic investigation of this syndrome. Indeed, both type and structure of symptoms are strikingly similar in Gulf war veterans and patients with macrophagic myofasciitis. Multiple vaccinations performed over a short period of time in the Persian gulf area have been recognized as the main risk factor for Gulf War syndrome. Moreover, the war vaccine against anthrax, which is administered in a 6-shot regimen and seems to be crucially involved, is adjuvanted by aluminium hydroxide and, possibly, squalene, another Th-2 adjuvant. If safety concerns about long-term effects of aluminium hydroxide are confirmed it will become mandatory to propose novel and alternative vaccine adjuvants to rescue vaccine-based strategies and the enormous benefit for public health they provide worldwide.

Cytokines are polypeptides produced by various cells, with key-roles in regulation of immune response, inflammation and hematopoiesis. Cytokine-producing cells in peripheral nerve include resident and recruited macrophages, lymphocytes, and likely mastocytes, Schwann cells, and probably neurons. Cytokines are instrumental in pathogenesis of peripheral neuropathies during nerve lesions and tissue repair. Tumor necrosis factor-alpha (TNF-alpha) injection into nerve induces Wallerian degeneration. In contrast, interleukin-1 (IL-1) promotes detersion by scavenger macrophages, and increased synthesis of neurotrophic factor (nerve growth factor--NGF--and leukemia inhibitory factor--LIF). Neurotrophic cytokines IL-6, LIF and transforming growth factor-beta 1 (TGF-beta 1) are overexpressed in nerve after experimental axotomy and promote axonal growth until axon/Schwann cell contact. In the course of inflammatory demyelinating neuropathies, proinflammatory cytokines induce vascular permeability and breakdown of blood nerve barrier (TNF-alpha, vascular endothelial growth factor/vascular permeability factor--VEGF/VPF), favor leukocyte transmigration into nerve, induce activation and proliferation of lymphocytes (IL-1, IL-2) and macrophages (gamma-interferon--IFN-gamma), and have a direct myelinotoxic activity (TNF-alpha and TNF-beta). In addition, the inflammatory process is likely favored by downregulation of the anti-inflammatory cytokine TGF-beta 1.

The Polyneuropathy, Organomegaly, Endocrinopathy, M protein, Skin changes (POMEMS) syndrome is a rare multisystem disorder of obscure pathogenesis, associated with osteosclerotic myeloma. Unlike multiple myeloma without neuropathy, circulating levels of proinflammatory cytokines (IL-1 beta, TNF-alpha IL-6) are increased in patients with POEMS syndrome. Sites of IL-1 beta production include lymph node and bone marrow tissues. These data support the view that pleiotropic effects of proinflammatory cytokines released secondary to a strong activation of the monocyte/macrophage system, take part in the multisystemic expression of the disease.