Hans Heiken

Reconstitution of NK cell activity in HIV-1 infected individuals receiving antiretroviral therapy.

We studied natural immunity mediated by natural killer (NK) cells in 62 HIV-1 infected individuals, 54 HIV-1 infected individuals receiving highly active antiretroviral therapy (HAART) for more than one year and 8 HIV-1 infected individuals without antiretroviral therapy. 22 individuals had a complete suppression of viral replication characterized by viral load values <50 copies/ml, whereas 32 individuals presented with persistent viral replication. The 8 untreated patients had an indication to start antiretroviral treatment. Lytic activity of NK cells was measured in a 51chromium release assay. In patients with persistent viral replication under HAART NK cell activity was significantly decreased compared to patients with effective control of HIV viremia. Patients with complete suppression of HIV replication displayed a similar NK activity to healthy control persons. Differences in antibody-dependent cellular cytotoxicity (ADCC) were not observed. Further studies will investigate whether decreased NK cell activity is a reason for or the consequence of persistent viral replication.

Exogenous HIV-1 Vpr disrupts IFN-α response by plasmacytoid dendritic cells (pDCs) and subsequent pDC/NK interplay

HIV Vpr is known for its immunomodulatory capacities including its impairment of NK cell functions. However, the role of pDCs in this context remains elusive. We show that synthetic Vpr substantially inhibits type I IFN production by pDCs without inducing apoptosis in pDCs. Furthermore, we found that exogenous Vpr compromises subsequent pDC/NK interplay as shown by diminished IFN-gamma production by NK cells. Thus, Vpr-mediated dysregulation of IFN-alpha and IFN-gamma production affects key components of the innate immune response supporting an essential role of Vpr in HIV pathogenesis.

Analysis of contemporary HIV/AIDS health care costs in Germany: Driving factors and distribution across antiretroviral therapy lines.

AbstractTo analyze contemporary costs of HIV health care and the cost distribution across lines of combination antiretroviral therapy (cART). To identify variations in expenditures with patient characteristics and to identify main cost determinants. To compute cost ratios between patients with varying characteristics.Empirical data on costs are collected in Germany within a 2-year prospective observational noninterventional multicenter study. The database contains information for 1154 HIV-infected patients from 8 medical centers.Means and standard deviations of the total costs are estimated for each cost fraction and across cART lines and regimens. The costs are regressed against various patient characteristics using a generalized linear model. Relative costs are calculated using the resultant coefficients.The average annual total costs (SD) per patient are &OV0556;22,231.03 (8786.13) with a maximum of &OV0556;83,970. cART medication is the major cost fraction (83.8%) with a mean of &OV0556;18,688.62 (5289.48). The major cost-driving factors are cART regimen, CD4-T cell count, cART drug resistance, and concomitant diseases. Viral load, pathology tests, and demographics have no significant impact. Standard non-nucleoside reverse transcriptase inhibitor-based regimens induce 28% lower total costs compared with standard PI/r regimens. Resistance to 3 or more antiretroviral classes induces a significant increase in costs.HIV treatment in Germany continues to be expensive. Majority of costs are attributable to cART. Main cost determinants are CD4-T cells count, comorbidity, genotypic antiviral resistance, and therapy regimen. Combinations of characteristics associated with higher expenditures enhance the increasing effect on the costs and induce high cost cases.

Normalization of cytomegalovirus-specific CD4 T cells in HIV-1-infected individuals receiving antiretroviral therapy.

HIV infection is characterized by a loss of immunological function and the development of severe opportunistic infections such as cytomegalovirus. To determine the frequency of cytomegalovirus-specific CD4 T cells in healthy and HIV-infected individuals, we examined peripheral blood mononuclear cells from 10 HIV-negative and 55 HIV-positive individuals for antigen-induced intracellular cytokine responses. We found that HIV suppression with antiretroviral therapy leads to a normalization of previously increased cytomegalovirus-specific CD4 T cells, indicating the efficient control of an opportunistic pathogen.

Progressive Reduction of CMV-Specific CD4+ T Cells in HIV-1 Infected Individuals During Antiretroviral Therapy

Visualization of antigen-specific T cells has become an important tool in studying immune responses. The aim of this study was to analyze CMV-specific CD4+ T cells in healthy and HIV-infected individuals. Peripheral blood mononuclear cells (PBMC) were examined for antigen-induced intracellular cytokine responses. We found significant numbers of CMV-specific CD4+ T cells detectable in most CMV-IgG+ HIV-1 infected individuals, whereas CMV-specific CD4+ T cells could not be demonstrated in CMV-IgG- patients. Median frequency of CMV-specific CD4+ T cells were lower in HIV-infected subjects who had been treated with highly active antiretroviral therapy (HAART) for more than 1 year than in untreated HIV-infected individuals. In patients under therapy for less than 1 year median CMV-specific CD4+ T cell responder frequency was higher than in subjects treated for more than 1 year but lower than in untreated subjects. HIV suppression with HAART might lead to a progressive reduction of CMV-specific CD4+ T cells indicating an efficient elimination of an opportunistic pathogen.

Immune restoration inflammatory syndromes

ZusammenfassungDer häufigere Einsatz immunsuppressiver Therapieverfahren, die Pandemie der HIV-Infektion und verbesserte Behandlungsmöglichkeiten Immunkompromittierter bewirken eine Zunahme der Prävalenz von Immundefekten. Die hochwirksame antiretrovirale Therapie (HAART) bewirkt eine Zunahme der Immunkompetenz bei HIV-Infizierten und dadurch den Rückgang von Morbidität und Mortalität. Durch die damit verbundene Immunrekonstitution können andererseits paradoxerweise opportunistische Infektionen oder Autoimmunerkrankungen exazerbieren. Aufgrund klinischer, pathophysiologischer und differenzialtherapeutischer Besonderheiten werden diese Krankheitsbilder als immunrekonstitutionelle inflammatorische Syndrome (IRIS) zusammengefasst. Die vorliegende Übersicht gibt einen Überblick über zugehörige Krankheitsbilder und macht Vorschläge zur Einteilung des Krankheitsbildes und zu dem therapeutischen Procedere.AbstractIncrease of prevalence of certain immunodeficiencies is caused by more frequent use of immunosuppresive treatment, by advances in supportive care of immunodeficient individuals and by the pandemic spread of HIV-infection respectively. Highly active antiretroviral treatment (HAART) is able to reconstitute the impaired immunity in the HIV-infected individual and therefore to reduce morbidity and mortality. On the other hand paradoxical exacerbation of inflammatory or opportunistic diseases may develop during immunoreconstitution. By their distinct pathophysiological, clinical and therapeutic particularities these disease have been summarized as Immune Restoration Inflammatory Syndromes (IRIS). This review summarizes the variety of immunoreconstitution disorders and describes possible diagnostic pitfalls. Potential therapeutic options and an algorythm for the classification of the syndrome are proposed.

Δ32 Polymorphism of the chemokine receptor CCR5 in a patient with multifocal motor neuropathy

32 POLYMORPHISM OF THE CHEMOKINE RECEPTOR CCR5 IN A PATIENT WITH MULTIFOCAL MOTOR NEUROPATHY In the pathogenesis of immune-mediated neuropathies, chemokines and their receptors play a crucial role in recruitment and activation of leukocytes into the peripheral nervous system (PNS).2,3,5 Here we describe a patient with a multifocal motor neuropathy (MMN) and a homozygous mutation for the 32 polymorphism of the CCR5 chemokine receptor. A 51-year-old man presented with progressive difficulties in carrying heavy bags, in fine motor skills with his right hand, and in walking, with a limited walking range of 50 meters. Neurological examination showed marked muscle atrophy of the right shoulder and upper-arm muscles and of the left leg. There was weakness of right arm elevation and extension and of left hip flexion and foot extension. Deep tendon reflexes were generally diminished, with flexor plantar responses. There was no sensory impairment. Nerve conduction studies showed conduction blocks in both median nerves and in the right ulnar nerve. Serum creatine kinase activity was slightly increased (277 U/L, normal 171 U/L) and anti-GM1 ganglioside antibodies (IgM subtype) tested positive with a titer of over 10,000 units (reference 800 units). Further diagnostic workup excluded other causes for peripheral neuropathy and MMN was diagnosed.4 Treatment with 0.4 g/kg of intravenous immunoglobulin (IVIg) daily for 5 consecutive days led to a marked improvement of muscle strength and unrestricted ambulation. The good clinical response was maintained by IVIg treatment with the same dose for 3 consecutive days after 8 weeks and by a third IVIg treatment after another 8 weeks with a reduced dose of 0.25 g/kg daily on 3 consecutive days. Before and after IVIg treatment we investigated the chemokine receptor expression profile on lymphocytes and monocytes by flow cytometry.7 As CCR5 expression was not detected on any mononuclear cell, we tested for the 32 polymorphism of the CCR5 receptor6 and found a homozygous 32 polymorphism mutation (Fig. 1). Expression of the chemokine receptors CCR1, CCR2, CCR4, CCR6, CCR7, and CXCR3 on CD4 and CD8 lymphocytes were not significantly changed by IVIg treatment or different from seven other patients with MMN without a homozygous mutation of the 32 polymorphism (Table 1). Expression of CCR5 on CD4 and CD8 lymphocytes in seven other MMN cases without a homozygous mutation of the 32 polymorphism did not significantly differ compared to healthy controls or other immune-mediated neuropathies (Table 1).7 The 32 polymorphism results in expression of a nonfunctional CCR5 protein and therefore individuals with the homozygous mutation are natural human knockouts for CCR5.1 Our patient with

The choice between a ritonavir-boosted protease inhibitor- and a non-nucleoside reverse transcriptase inhibitor-based regimen for initiation of antiretroviral treatment – results from an observational study in Germany

BackgroundThis study aims at identifying predictors of the treatment decision of German physicians with regard to a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a ritonavir-boosted protease inhibitor (PI/r) -based initial treatment regimen.MethodsThe study is based on a sub analysis of a nation-wide multi-centre, non-interventional, prospective cohort study. 133 patients were identified, who received antiretroviral first-line therapy. By means of a logistic regression, factors that determine the treatment strategy for treatment-naïve patients were analysed.ResultsCompared to patients receiving a NNRTI-based initial regimen, patients treated with PI/r are slightly younger, less educated, in a later stage of HIV and have more concomitant diseases. Regression analysis revealed that being in a later stage of HIV (CDC-C) is significantly associated with a PI/r-based treatment decision.ConclusionsOur analysis is the first study in Germany investigating sociodemographic and disease-specific parameters associated with a NNRTI- or a PI/r-based initial treatment decision. The results confirm that the treatment decision for a PI/r strategy is associated with disease severity.