Emanuella Morra

Anti-HIV effects of chloroquine: inhibition of viral particle glycosylation and synergism with protease inhibitors

ObjectiveWe tested the effects of chloroquine (CQ) on glycosylation of HIV particles and in combination with protease inhibitors (PIs) on HIV replication and on P-glycoprotein (P-gp)/multidrug resistance protein-1 (MRP1). DesignCD4+ cell lines were infected with laboratory strains and peripheral blood mononuclear cells were infected with primary isolates for evaluation of the anti-HIV effects. Peripheral blood lymphocytes were evaluated for of P-gp and MRP1 functions. MethodsHIV replication was assessed by enzyme-linked immunosorbent assay. HIV glycosylation was measured by metabolic labeling of viral particles with [3H] glucosamine. Synergism was tested using isobolograms. P-gp and MRP1 functions were assayed using rhodamine 123 (Rh123) and carboxyfluorescein (CF) efflux assays, respectively. ResultsCQ alone inhibited HIV replication and glycosylation in a dose-dependent manner. In combination with indinavir (IDV), ritonavir, or saquinavir (SQV), CQ had a synergistic effect at concentrations found in plasma of subjects receiving malaria prophylaxis. CQ decreased the 50% effective concentration of IDV in primary isolates from Africa and restored the response to IDV or SQV in 3 PI-resistant isolates. CQ increased the block of Rh123 and CF efflux activity exerted by PIs. ConclusionThe inhibitory effects of CQ on HIV glycosylation are associated with synergistic effects in combination with PIs. The CQ/PI combination exerts combined inhibitory effects on P-gp and MRP1 function.

Role of iron metabolism and oxidative damage in postmenopausal bone loss

It has been suggested that iron-deficient rats have lower bone mass than iron-replete animals, but a clear association between bone and iron repletion has not been demonstrated in humans. A growing body of evidences also suggests a relation between lipid oxidation and bone metabolism and between iron metabolism and LDL oxidation. Iron availability to cells also depends on haptoglobin (Hp) phenotypes. Hp has also important antioxidant properties according to its phenotype, hence we evaluate whether Hp phenotype could influence bone density, iron metabolism and lipid oxidation. This cross-sectional study enrolled 455 postmenopausal women affected by osteoporosis (260) or not (195). Bone mineral density, markers of bone and iron metabolism, levels of oxidized LDL (oxLDL) and Hp phenotype were measured in all the subjects. Hp 1.1 and 2.2 frequency was higher and Hp 2.1 was lower in the patients with fragility fractures (80) compared with the controls. We therefore evaluate different Hp phenotypes as risk or protective factors against fragility fracture: Hp 2.1 is a protective factor against fracture while 1.1 is an important and 2.2 a moderate risk factor for fragility fractures. Lower serum iron was associated with elevated transferrin in patients with Hp 1.1; moreover patients had relative iron deficiency compared with the controls and fractured patients had higher level of oxLDL. We found that both iron metabolism and oxLDL varies according to Hp phenotypes and are predictive of bone density. Our data indicate that Hp 2.1 is a protective factor for fragility fractures, depending on its role on iron metabolism and its antioxidant properties.

Serum Citrate Levels, Haptoglobin Haplotypes and Transferrin Receptor (CD71) in Patients With HIV-1 Infection

AbstractBackground: The progression of HIV-1 infection towards its more advanced stages is accompanied by changes in iron metabolism and increased body iron stores. Patients and Methods: Given the ability of HIV to alter iron metabolism, we studied the principal (transferrin system) and alternative (citrate system) iron pathways in a group of 65 HIV-infected patients (symptomatic stage B1–B3) and in a group of 36 healthy seronegative individuals. We determined serum citrate levels, haptoglobin (Hp) haplotypes, expression of transferrin receptor (CD71) on cell lines infected with HIV-1 as well as iron markers including blood iron, transferrin and ferritin. Results: Our data showed decreased serum citrate levels in the HIV-infected patients compared to controls (92.9 ± 22.4 μM/l vs 126.2 ± 29.2 μM/l; p < 0.01). In particular, the serum citrate levels negatively correlated with HIV-1 RNA copy number (mean: 2.53 ± 1.88 × 105/ml, rs = 0.70, p < 0.01) and positively correlated with CD4+ T-lymphocyte count (mean: 241 ± 168/ml, rs = 0.64, p > 0.05). Accordingly, blood iron, transferrin and red cell concentrations were lower in HIV-infected patients compared to the controls, whereas serum ferritin levels were higher in HIV-infected patients. Moreover, the Hp haplotype distribution showed significant differences only in the group of HIV-infected patients (p = 0.02; χ2 test). Conclusion: Our results show that iron metabolism is altered in patients with HIV-1 infection. The alternative pathway (citrate system) is particularly affected, since when citrate levels are low, both aconitase activity and HIV-1 replication need iron.

Haptoglobin genotype as a risk factor for postmenopausal osteoporosis

Editor—Some epidemiological and experimental data have shown a correlation between iron metabolism and calcium, phosphate, and magnesium turnover.1 2 In particular, previous reports have shown that iron availability can play a fundamental role in bone metabolism and that iron depletion can lead to bone demineralisation. For example, in patients who underwent gastrectomy3-5 or in rats treated similarly,6 osteoporosis was accompanied by laboratory and clinical signs of iron deficiency and was prevented by the administration of fructo-oligosaccharides, a substance that promotes iron absorption from the gut. In oophorectomised rats (a condition mimicking the oestrogen levels commonly found in the menopause), a wide range of cells, including osteoblasts, displayed a reduced number of transferrin receptors and hence a reduced iron uptake.7 In humans, it has been assessed that out of 14 nutrients tested (including calcium), iron was the best positive predictor of BMD in the femoral neck,8 and furthermore a negative correlation between ascorbic acid content of the diet and osteoporosis has been found9 10; it is notable that ascorbic acid in the diet affects iron absorption increasing it by a factor of 2-3. A severe nutritional iron deficiency anaemia provokes significant alterations in the metabolism of calcium, phosphorus, and magnesium in rats with a noticeable degree of bone demineralisation, even in the presence of normal serum levels of calcium, phosphorus, and magnesium.1 On the basis of the above evidence, we searched for a genetic …

Iron metabolism markers and haptoglobin phenotypes in susceptibility to HSV-1 or/and HSV-2 lesion relapses

Different haptoglobin (Hp) phenotypes play a role in several pathologic processes including infectious diseases. In order to evaluate the role of iron storage and metabolism in susceptibility to herpetic manifestations, we studied the frequency of the Hp phenotypes and iron metabolism in patients affected by H. Simplex virus 1 or 2 (HSV‐1 or HSV‐2), compared with controls. Hp phenotype and iron metabolism were determined in 100 patients with recurrent HSV‐1 or HSV‐2 manifestations during the relapses, and in 110 healthy subjects. The frequencies of the three Hp phenotypes in the patient group compared to the control group were 18% versus 14.5% p = NS for Hp 1.1, 25% versus 40% p = 0.03 for Hp 2.2 and 57% versus 45.5% p = NS for Hp 2.1. All iron metabolism parameters tested showed significant differences between patients and controls; haemoglobin (Hb), ferritin, and serum iron were lower, while transferrin was higher in the patients than in controls. Reductions in iron availability may be a risk factor for relapsing lesions of HSV‐1 or HSV‐2. Hp 2.2 phenotype may offer some protection against the recurrence of Herpes labialis or genitalis manifestations. Copyright