Excessive innate immune response and mutant D222G/N in severe A (H1N1) pandemic influenza.

AIM: Explore the role of viral factors and immune response in patients with severe pandemic pdmH1N1 illness without significant co-morbidity. MATERIALS: Seven patients with pdmH1N1 influenza, bilateral chest X-rays infiltrates, requiring mechanical ventilator support were consecutively recruited. Seven age- and gender-matched healthy individuals served as controls. RESULTS: Four patients were viremic, two with the mutant D222G/N pdmH1N1.Microarray analyses of peripheral blood leukocytes suggested a marked granulocytes activation, but no up-regulation of inflammatory cytokine mRNA. Patients with severe pdmH1NI had a marked systemic complement activation, and in contrast to the lack of cytokine mRNA up-regulation in blood leukocytes, plasma levels of a broad range of inflammatory mediators, including IP-10, and mediators involved in pulmonary remodelling were markedly elevated. Patients with mutant virus had particularly high IP-10 levels, and the most pronounced complement activation. CONCLUSIONS: In severe pdmH1N1, viremia was common and the D222G/N mutant was found in half of the viremic patients. Host immune response was characterized by strong activation of the innate immune system, including complement and granulocytes activation, increased serum levels of inflammation and pulmonary remodelling markers, possibly contributing to the observed tissue damage. However, few patients were included and further studies are needed to characterize the immune response in severe pdmH1N1 infection.

Long term adverse effects related to nucleoside reverse transcriptase inhibitors: clinical impact of mitochondrial toxicity.

Antiretroviral treatment (ART) has provided excellent clinical efficacy in HIV infection, and individuals treated for HIV might therefore expect normal duration of life. However, this enthusiasm might be moderated by some devastating long-term adverse effects that are frequently observed in HIV-infected individuals, phenomena that may be even more pronounced as the HIV-infected populations become older and therefore perhaps more susceptible to some of these adverse effects. We here review the clinical impact of mitochondrial toxicity giving rise to many of the adverse effects caused by ART.

Mitochondrial toxicity in HIV-infected patients both off and on antiretroviral treatment: a continuum or distinct underlying mechanisms?

Mitochondrial toxicity contributes to serious adverse effects observed in HIV-infected individuals treated with nucleoside reverse transcriptase inhibitors (NRTIs). However, similar mitochondrial abnormalities have recently been found even in treatment-naive patients, suggesting that chronic HIV per se could contribute to the toxicity observed in NRTI-exposed individuals. This review gives a current status of the field, with particular focus on recent observations suggesting that distinct mechanisms might cause such toxicity in both NRTI-exposed individuals and those naive to antiretroviral treatment.

Distinct mechanisms for mitochondrial DNA loss in T and B lymphocytes from HIV-infected patients exposed to nucleoside reverse-transcriptase inhibitors and those naive to antiretroviral treatment.

OBJECTIVE: Mitochondrial DNA (mtDNA) loss in peripheral blood mononuclear cells (PBMCs) has been found in both nucleoside reverse-transcriptase inhibitor (NRTI)-exposed and antiretroviral therapy (ART)-naive patients with human immunodeficiency virus (HIV) infection. Persistent immune activation might play a role in this phenomenon in HIV-infected, ART-naive patients. PBMC subsets with differential growth kinetics were therefore purified to study this similarity. METHODS: CD4(+) and CD8(+) T cells, CD19(+) B cells, and CD14(+) monocytes were purified from PBMCs. mtDNA levels were quantified using real-time polymerase chain reaction and compared among the 2 groups of HIV-infected patients and a group of HIV-negative control subjects. mtDNA levels in a separate group of ART-naive patients stratified by the rate of disease progression were also evaluated with respect to their relationship to immune-activation markers (i.e., CD38 and programmed cell death-1 [PD-1]) on CD8(+) T cells and the rate of CD4(+) T cell loss. RESULTS: mtDNA levels in CD8(+) T cells and B cells from 15 ART-naive patients were approximately 50% less than those observed for 14 control subjects (P < or = .01). mtDNA levels in all lymphocyte subsets correlated negatively with CD38(+)PD-1(+) expression (r= -0.66 P < -0.9; P < or = .03), and mtDNA levels in B cells correlated with the rate of CD4(+) T cell loss (r =0.66; P< .3). In 17 HIV-infected, NRTI-exposed patients, mtDNA loss was observed in both T cell subsets (P < or = .02) and was most pronounced in patients who received didanosine (P < or = .002). CONCLUSIONS: In HIV-infected, ART-naive patients, mtDNA loss was found in CD8(+) T cells and B cells. These losses correlated with immune activation and, in B cells, with the rate of CD4(+) T cell loss. In patients receiving ART, only T lymphocytes had reduced mtDNA levels. This finding was probably associated with NRTI use, because it was most pronounced in patients with a history of didanosine exposure.

Insulin resistance is affected by increased levels of plasma lactate but not mitochondrial alterations in skeletal muscle in NRTI-exposed HIV-infected patients.

PURPOSE: To explore the relations between insulin resistance, plasma lactate, and mitochondrial (mt) DNA alterations in skeletal muscle in HIV-infected patients treated with nucleoside reverse transcriptase inhibitors (HIV+NRTI+). METHOD: Insulin resistance was estimated using the homeostatic model assessment (HOMA-IR). Mitochondrial dysfunction was determined by plasma lactate at rest and after subanaerobic exercise, mitochondrial/nuclear DNA (mt/nDNA) ratio, and mtDNA deletions in skeletal muscle. RESULTS: HIV+NRTI+ patients (n = 27) had higher levels of HOMA-IR, higher lactate at rest as well as after exercise, and more frequent mtDNA deletions and decreased mt/nDNA ratios compared with controls (n = 15). Only in HIV+NRTI+ patients, HOMA-IR correlated with resting lactate (r = 0.5, p = .02) and probably also lactate 3, 5, and 8 minutes after exercise (r = 0.4; p = .075, p = .048, and p = .056, respectively). In contrast, neither HOMA-IR nor the lactate levels correlated with mt/nDNA ratio and mtDNA deletions in skeletal muscle in HIV+NRTI+ patients (r < 0.1, p > .6), whereas resting lactate correlated with mt/nDNA ratio in HIV seronegative controls (r = -0.7, p = .02). CONCLUSION: In HIV+NRTI+ patients, both resting and postexercise levels of lactate were related to insulin resistance rather than mtDNA alterations in skeletal muscle.

Mitochondrial (mt)DNA changes in tissue may not be reflected by depletion of mtDNA in peripheral blood mononuclear cells in HIV-infected patients.

OBJECTIVES: Most data on mitochondrial toxicity have been derived from peripheral blood mononuclear cells (PBMCs). However, whether mitochondrial DNA (mtDNA) content in PBMCs reflects the mitochondrial state in tissues remains elusive. We report herein on mitochondrial toxicity in skeletal muscle in HIV-infected patients naive to antiretroviral treatment (ART [HIV+ART-naive]; n = 10) patients exposed to nucleoside reverse transcriptase inhibitors (NRTIs [HIV+NRTI+]; n = 24) and healthy controls (n = 11), and compare these tissue data with mtDNA in PBMCs. METHODS: Muscle biopsies were examined for (i) mtDNA and nuclear DNA (nDNA) content using TaqMan real-time PCR system, (ii) mtDNA deletions using long expand PCR with subsequent gel electrophoresis, and (iii) mitochondrial myopathy expressed as cytochrome c oxidase (COX)-deficient muscle fibres. RESULTS: The mt/n DNA ratio in muscle from HIV+NRTI+ patients was reduced compared with HIV-negative controls (P = 0.028). Moreover, mtDNA deletions were more frequent in HIV+NRTI+ patients than in both HIV-negative controls (P = 0.009) and HIV+ART-naive patients (P = 0.005). HIV+NRTI+ also tended to have more COX-deficient fibres than HIV-negative controls (P = 0.076). COX-deficient fibres were positively correlated with mtDNA deletions in HIV+NRTI+ patients (r = 0.83, P < 0.001). Patients with current use of didanosine (ddl) had more frequent mtDNA deletions and COX-deficient fibres than HIV+NRTI+ not on current treatment with ddl. It should be noted that mitochondrial alterations were not correlated with mtDNA/cell in PBMCs in any group. CONCLUSIONS: In skeletal muscle, HIV+NRTI+ had a reduced mt/n DNA ratio, more frequent mtDNA deletions and possibly more COX-deficient muscle fibres than HIV-negative controls. However, the mtDNA/cell in peripheral blood was decreased in both HIV+NRTI+ and HIV+ART-naive patients. Thus, mtDNA in peripheral blood may not be a relevant marker of mitochondrial toxicity in organ-specific tissue.

Psoas abscess diagnosed at a Northern university hospital.

Abscess of the psoas muscle is an infrequent diagnosis at hospitals in Northern countries. We report on 16 patients who had this diagnosis during the period 1991-2001. Eight patients were immigrants who had previously been healthy and most of them had experienced symptoms for approximately 1 y. MRI or CT scans revealed spondylodiscitis in 6 of these patients and Mycobacterium tuberculosis was identified as the causative agent. With the exception of 1 patient who was exclusively treated with antituberculous agents, all 8 immigrant patients were successfully treated with antituberculous agents in addition to percutaneous drainage. The other 8 patients were Norwegians, 4 of whom had underlying conditions such as diabetes mellitus or drug abuse. The causative microorganisms were Staphylococcus aureus or Streptococcus spp., with the exception of M. tuberculosis in 1 case. The Norwegian patients had a more acute history of symptoms than the immigrant patients and 2 of them were in a septic condition on admittance. Two of the Norwegians died of serious infection; 5 were successfully treated with percutaneous drainage in addition to antibiotics and 1 was treated exclusively with antibiotic agents. The clinical history and microorganism associated with psoas abscess seemed to depend on whether or not the patient was an immigrant. Owing to increasing immigration, diagnosis of psoas abscess should be taken into account in Northern countries.