oa Editorial[Hot topic: Targets of Metabolic Toxicity of HIV Antiretroviral Drugs: The Multiple Roads to Lipodystrophy and Metabolic Syndrome (Executive Editors: Pere Domingo and Francesc Villarroya)]

The introduction of highly active antiretroviral therapy the mid-1990s, based on treating HIV-1 infected patients with a combination of distinct antiretroviral drugs, resulted in dramatic amelioration of patient mortality and morbidity. Soon afterwards, however, prominent systemic metabolic alterations were observed in a significant subset of HIV-1-infected, antiretroviral-treated patients, often in combination with prominent alterations in body-fat distribution -the so-called “lipodystrophy syndrome”[1]. The systemic metabolic alterations, characterized by insulin resistance and dyslipidemia were reminiscent of the “metabolic syndrome”, a pattern of metabolic disturbances common in the Western populations and often associated with obesity Lipodystrophy in these patients was characterized by lipoatrophy in peripheral areas (e.g., face, arms, legs), visceral adipose tissue lipohypertrophy and even lipomatosis, although not all these alterations necessarily occurred simultaneously in the same patient. These alterations soon became a major concern as side effects of antiretroviral treatment in HIV-1 patients for several reasons. First, metabolic disturbances were associated with increased risk of cardiovascular disease or diabetes. Moreover, the disfiguration caused by the loss of facial adipose tissue often led to psychological distress and sometimes to poor adherence to treatment regimens. The recognition of lipodystrophy in HIV-1-infected patients undergoing antiretroviral treatment coincided with the initiation of the use of HIV-1 protease inhibitors as antiretroviral drugs; thus, this type of drugs was initially considered primarily responsible for the syndrome. However, it has become evident that these alterations cannot be attributed to a single type of drug. In fact, they are the result of a complex interplay between the side effects of distinct antiretroviral drugs and the underlying HIV-1 infection status in a given patient. Years of active research into this syndrome has provided a wealth of information that is helpful for understanding the causes of the syndrome, improving drug design so as to minimize the anatomical and metabolic alterations, and developing co-treatment strategies to prevent, mitigate or reverse these alterations. However, despite the fact that recent antiretroviral treatment regimens have reduced the appearance of full-blown lipodystrophy, we are still far from a full resolution of this health problem. The current issue provides an updated review of the major mechanisms that contribute to the etiopathogenesis of lipodystrophy and associated metabolic alterations in HIV-1-infected patients undergoing antiretroviral treatment. Feeney and Mallon [2] provide an update of the role of mitochondrial toxicity in the distinct aspects of the syndrome. An alteration in mitochondrial function associated with the mitochondrial DNA depletion caused by some antiretroviral drugs was among the first hypothesis to explain the lipodystrophy syndrome in these patients. After several years of intensive investigation, mitochondrial toxicity is still viewed as a major component of the alterations that lead to the lipodystrophy syndrome, although current thinking has evolved beyond the simple early models based only on mitochondrial DNA depletion. Recent years have seen a growing recognition of the multiple functions served by mitochondria in addition to their classical ATP-producing role, including their involvement in oxidative stress, intracellular signaling, an control of apoptosis [3]. As reviewed by these authors, these developments have contributed to our understanding of the role of mitochondrial dysfunction in the HIV lipodystrophy syndrome. The contribution of Caron-Debarle and co-workers [5] is a state-of-the-art review of molecular and cellular aspects of the alterations in adipocyte biology associated with this syndrome. Research in lipodystrophy and associated metabolic diseases in HIV-1-infected patients has coincided with intense research on adipose tissue biology, fueled by both basic science research and obesity research [4]. The establishment of the major molecular mechanisms of adipose cell differentiation and the recognition of the endocrine role of white adipose tissue have helped to clarify the molecular and cellular bases of adipose tissue alterations in HIV-1-infected patients. Conversely, research on HIV-1 lipodystrophy has identified novel, and often unpredicted, aspects of adipose tissue biology and pathophysiology, revealing potential drug targets that specifically address adipose tissue function. Stankov and Behrens provide an overview of the role of inflammation in HIV-1 lipodystrophy and associated metabolic diseases [6]. The recognition of local inflammation in adipose tissue and its consequences for systemic metabolism, via altered release of regulatory proinflammatory cytokines and adipokines, has been a central concept in recent studies on the relationship between the metabolic syndrome and dysregulation of adipose tissue in obesity [7]. Multiple emerging lines of evidence reveal a pro-inflammatory environment in the adipose tissue of HIV-1-infected, antiretroviral-treated patients, with lipodystrophy and related metabolic alterations. The presence of proinflammatory features in common between obesity and HIV-1 lipodystrophy may seem paradoxical at a first glance. Lipotoxicity is a developing concept for explaining the etiopathogenesis of the metabolic syndrome [8]. It provides a novel explanation for the relationship between adipose tissue expandability and metabolic damage in non-adipose tissues. Studies of lipodystrophies of genetic origin upheld the development of the lipotoxicity theory. The contribution of Giralt and co-authors [9] develops the potential of the lipotoxicity theory for explaining the multiple features of metabolic alterations in HIV-1-infected patients and summarizes the experimental and clinical evidence in support of a “lipotoxicity explanation” for these alterations. Finally, Veloso and co-workers provide a summary of our current understanding of the role of genetic background in determining the differential responsiveness of an individual patient's metabolism to the secondary effects of antiretroviral treatment [10]. Pharmacogenetics is increasingly taking center stage in efforts to account for the variability and complexity of individual responses to drugs, not only in terms of the efficacy of drugs for their primary therapeutic purpose but also in relation to the differential appearance of secondary effects. This contribution summarizes the current state of pharmacogenomics knowledge in relation to the metabolic side effects of anti-retroviral drugs for the treatment of HIV-1-infected patients. Collectively, the distinct contributions to this special issue provide a unique overview of the current knowledge of the complex issue of metabolic disturbances in HIV-1-infected patients following antiretroviral therapy. The multidisciplinary, but integrated, views provided in this special issue should substantially advance efforts to prevent and treat these secondary effects, and aid in the design of drugs minimizing metabolic alterations and lipodystrophy. We acknowledge the referees and Editorial Board members who have helped the produce this issue....