Comparative Transcriptional Profiling in HIV-Infected Patients Using Human Stress Arrays: Clues to Metabolic Syndrome

Highly active antiretroviral therapy (HAART therapy) for HIV-1 infection has significantly increased the survival and quality of life of patients with this disease. However, in several epidemiological studies the onset of metabolic syndrome is a phenomenon reported to be extremely frequent. In the present study, genes involved in the molecular cascade responsible for the alteration of fat tissue and of lipid and glucose metabolism in patients with HIV-1 infection treated with antiretroviral therapy were identified. Towards this goal, hybridization using Atlas cDNA Expression Arrays allowed simultaneous monitoring of the expression levels of approximately 250 genes and identification of a panel of changes in relation to different therapeutic groups and in the presence of metabolic syndrome, with some genes being up-regulated, while others are down-regulated in the different subgroups of patients. The results of this analysis have shown a panel of transcriptional changes associated with oxidative stress mechanisms that provide a basis for further studies on understanding of mechanisms that, in vivo, are the foundation the metabolic disorders in patients with HIV infection. Highly active antiretroviral therapy (HAART therapy) for HIV-1 infection has significantly increased the survival and quality of life of patients with this disease. However, some side effects are so relevant that they can influence the health and social life of patients (1, 2). Among these side-effects there is a syndrome characterized by fat redistribution (lipodystrophy), and an abnormal lipid and glucose profile. This phenomenon is generally defined as HIV-related metabolic syndrome, even in the absence of a universally accepted definition and well-defined clinical and laboratory parameters (3, 4). Lipodystrophy is commonly meant as a condition characterized by reduction of peripheral fat tissue (arms, legs, face etc.), compared with a central type of fat accumulation ("buffalo's back", abdomen), and it is frequently associated with lipid (cholesterol and triglycerides) and glucose (low glucose tolerance, hyperglycemia, diabetes) alterations (5, 6). In several epidemiological studies the onset of metabolic syndrome is a phenomenon reported to be extremely frequent, with an incidence reaching, in some cases, even 83% of patients treated with HAART (7, 8). Several studies have shown that two classes of transcription factors are involved in lipogenesis: CCAAT/enhancer-binding proteins (C/EBPs) (9) and peroxisome proliferator-activated receptors (PPAR) (10), which belong to the classes of transcription factors leucine zipper and nuclear hormone receptors respectively. (11, 12). Following the stimulus to differentiate, these two classes of transcription factors activate a cascade of genes that initially induce a mitotic stimulus followed by the activation of several genes specific for adipogenesis, which contribute mainly to the acquisition of the mature adipocytic phenotype. It has also been demonstrated that in patients treated with HAART, there was an alteration in the differentiation from preadipocytes to adipocytes mediated by adipogenetic transcription factors such as C/EBPα and PPARγ (13). This phenomenon could be the consequence of an enhanced antagonist effect of C/EBPβ and could have as a consequence an increase of the apoptosis of adipocytes that could interfere with preadipocyte differentiation. Drawing from this background, we decided to identify genes involved in the molecular cascade responsible for the alteration of fat tissue and of lipid and glucose metabolism in patients with HIV-1 infection treated with antiretroviral therapy.