Thus, HA might not only stimulate expression of the provirus, but also affect the viability and infectivity of the released virions. A similar inhibition of HIV-1 by reactive oxygen species was indeed shown in the case of bleomycin (Georgiou et al., 2004). Heme oxygenase has been suggested to exert various immunoregulatory effects on innate and adaptive immune cells, and to inhibit pathogenesis of several immune-mediated inflammatory diseases Cilengitide in vitro (Soares et al., 2009). Further, analysis of HO-1 promoter polymorphism revealed that Caucasian HIV-1-infected patients who maintain low levels of immune activation and control

HIV-1 viral loads to undetectable levels are more likely to possess a specific microsatellite (GT)n repeat and two single nucleotide polymorphisms in HO-1 promoter region Selleckchem AZD8055 that favor enhanced HO-1 gene expression ( Seu et al., 2009). The ability of cells to become activated remained unaffected by HA as demonstrated by expression of the early activation marker CD69, characterized by flow cytometry. Since the activation of T-cells constitutes an essential component of immune responses to the virus itself as well as to other infections, we consider the finding that HA does not seem to generally decrease the activation of T-cells as important. Moreover, HA did not induce any global activation of T-cells either; this finding is significant as well, since a nonspecific

T-cell activation and release of proinflammatory cytokines should be avoided. The effect of HA thus could be compared to the effect of 5-hydroxynaphthalene-1,4-dione, a compound recently described to reactivate the latent provirus without cellular activation (Yang et al., 2009). In vivo, HIV-1 infection can coincide with several conditions that lead to acute or chronic hemolysis that could cause a similar exposure to extracellular heme as does administration of HA. These conditions include genetically determined glucose-6-phosphate dehydrogenase deficiencies, sickle cell anemia, thalasemia or other hemoglobinopathies as well as various other diseases involving hemolytic episodes or chronic hemolysis, especially malaria ( Lopez

et al., 2010 and Pamplona et al., 2009). It would be worthwhile to determine a possible mafosfamide correlation of HIV-1/AIDS progression with these conditions. However, the situation is complex and therapeutic interventions, namely iron supplementation, could strongly affect the fine balance of pro-oxidative and anti-oxidative agents. In clinics, HA is used to treat acute attacks of hepatic porphyrias. The mean maximum plasma levels of heme after a single dose of HA 3 mg/kg body weight was determined as 60 μg/ml (corresponds to 2.4 μl/ml of HA), with a plasma half-life of 10.8 h and a distribution volume of 3.4 L (Tokola et al., 1986). The concentrations of HA used throughout this paper are thus very close to the levels achieved in clinics.