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June 27, 2007 EUROPEAN JOURNAL OF MEDICAL RESEARCH 23 Die analysierten Escape Mutationen beeinträchtigen die virale Replikation teilweise dramatisch und benötigen zur Wiederherstellung der Fitness kompensatorische Mutationen. Mechanistisch zeigte sich für diese Virusvarianten eine veränderte Abhängigkeit von dem zellulären Protein Cyclophyllin A (CypA), das normalerweise für eine erfolgreiche Infektion notwendig ist. Die mit HLA-B57 assoziierten Mutationen gingen mit einer Reduktion der Bindungskapazität des Capsids für CypA einher und niedrigere CypA-Konzentrationen waren für eine effektive Replikation ausreichend. Im Falle der B27- Escape Mutationen fungierte CypA sogar als Restriktionsfaktor, in dessen Präsenz keine Replikation stattfinden konnte. Diese Daten verdeutlichen, dass wichtige Wechselwirkungen zwischen Capsid und Proteinen der Zielzelle durch CTL Escape verändert werden. Strukturelle und funktionelle Einschränkungen bei der Selektion für Escape Mutationen verkleinern die virale Variationsbreite und führen gleichzeitig zu Mutanten mit eingeschränkter Fitness. Die Identifizierung weiterer Escape Mutationen in Gag, die mit einer Fitnessreduktion einhergehen oder die die Interaktion zwischen Capsid und zellulären Proteinen verändern, kann dazu beitragen, Zielstrukturen für effektive Impfstoffe zu charakterisieren. F. Immunologie F.ER.2 Immune weapons in HIV-induced neuropathogenesis Speth C. 1 , Hagleitner M. 1 , Wehinger A. 1 , Mohsenipour I. 2 , Arendt G. 3 , Dierich M.P. 1 , Maier H. 4 1 Medizinische Universität Innsbruck, Department für Hygiene, Mikrobiologie und Sozialmedizin, Innsbruck, Austria, 2 Medizinische Universität Innsbruck, Department für Neurochirurgie, Innsbruck, Austria, 3 Heinrich-Heine- Universität, Düsseldorf, Germany, 4 Medizinische Universität Innsbruck, Institut für Pathologie, Innsbruck, Austria Objectives: Complement synthesis and astrocytic phagocytosis are the most important local immune weapons in CNS and form an interactive network. This mutual immune network can limit viral spreading and virus-induced neural damage. Since the spontaneous complement production in the brain is low the expression level of complement in the virus-infected brain is an important parameter to evaluate the effectiveness of innate immune response. Therefore we quantified cerebral complement concentrations in HIV-infected patients and investigated the effect of complement on astrocytic phagocytosis. Methods: The expression of complement was analysed immunohistochemically in post-mortem brain tissue derived from HIV-infected patients and compared to control tissue from uninfected individuals. Phagocytosis by astrocytes was quantified using fluorescent opsonized beads. Results: The immunohistochemical analysis showed a strong upregulation of complement factors in the brain parenchyma of HIV-infected patients. Whereas only weak spontaneous complement expression was detected in uninfected control brains, a strong signal was obtained in the tissue of HIV-infected patients. All resident cell types (astrocytes, microglia, oligodendrocytes and neurons) contributed to the local complement synthesis with differences between the various complement factors. The increase of complement production seems to be an early event in HIV-induced neuropathogenesis, which starts already before the appearance of any neuropathological signs. No excessive degradation of complement was visible, indicating that the complement cascade is a functional immune weapon in the HIV-infected brains. This is underlined by the finding, that opsonization of latex beads with CSF from HIV-infected individuals supports the phagocytosis by infiltrating granulocytes. However, phagocytosis by resident astrocytes is inhibited by high complement amounts, indicating a bivalent role of complement in HIV-induced neuropathogenesis. Conclusion: Our data suggest that HIV infection of the brain induces local synthesis of complement factors. Thus, complement can play an important role as antiviral weapon. However it also inhibits local phagocytosis and thus support viral spreading and neurodegeneration. F.ER.3 Die Kontroverse um die HIV-spezifische CD8-T-Zellantwort Draenert R. 1 1 Ludwig-Maximilians-Universität, Medizinische Poliklinik, München, Germany Als chronische Virusinfektion wird die HIV-Virämie vor allem durch die HIV-spezifische CD8-T-Zellantwort kontrolliert. Schon 1987 wurden erstmals virus-spezifische CD8-T- Zellantworten im Blut von Infizierten nachgewiesen. Seither wird dieses Gebiet intensiv beforscht. Verbesserte Nachweismethoden zeigten, dass die HIV-spezifische CD8-T-Zellantwort sehr breit und individuell unterschiedlich ist. Alle exprimierten HIV-Proteine dienen als CD8-Epitope, wobei Gag und Nef am stärksten immunogen sind. Dies gilt gleichermaßen für alle untersuchten Ethnizitäten. Die Breite der CD8- T-Zellantwort ist abhängig vom Krankheitsstadium und dem Zeitpunkt des Therapiebeginns. In der akuten HIV-Infektion gibt es nur wenige CD8-T-Zellantworten, am wenigsten bei denen, die früh mit der Therapie begonnen haben. Selbst im weit fortgeschrittenen Krankheitsstadium können teilweise starke und breite CD8-T-Zellantworten gefunden werden. Gerade letzt genannte Tatsache ließ Zweifel an der Effektivität der CD8-T-Zellantwort aufkommen. So zeigte sich, dass es keine Korrelation gibt zwischen der Höhe oder der Breite der HIV-spezifischen CD8-T-Zellantwort und der Viruslast oder der Helferzellzahl. Dies führte zu der Untersuchung von verschiedenen Effektorfunktionen und phänotypischen Markern. Klare Unterschiede zwischen Personen, die die Virämie ohne antiretrovirale Therapie kontrollieren, und solchen, die in der Erkrankung fortschreiten, fanden sich für den Aktivierungszustand der CD8-T-Zellen und der Expression des death-rezeptors PD-1. Insgesamt könnte dies bedeuten, dass virus-spezifische CD8-T-Zellen mit zunehmender Dauer der Erkrankung an Effektivität verlieren und funktionslos werden. Dieser Vortrag soll einen kurzen Überblick geben über den Stand der Forschung hinsichtlich HIV-spezifischer CD8-T- Zellantworten und deren Bedeutung für die Impfentwicklung.
24 EUROPEAN JOURNAL OF MEDICAL RESEARCH June 27, 2007 F.ER.4 Increased IFN-alpha expression in circulating plasmacytoid dendritic cells of HIV-1 infected patients despite selective loss Lehmann C. 1 , Taubert D. 2 , Hartmann P. 1 , Fätkenheuer G. 1 , van Lunzen J. 3 , Stellbrink H.-J. 3 , Gallo R.C. 4 , Romerio F. 4 1 Klinikum der Universität zu Köln, Klinische Infektiologie, Köln, Germany, 2 Klinikum der Universität zu Köln, Institut für Pharmakologie, Köln, Germany, 3 Medical Center Hamburg-Eppendorf and Heinrich-Pette-Institute for Experimental Virology and Immunology, Hamburg, Germany, 4 University of Maryland, Institute of Human Virology, Baltimore, United States of America Objective: Plasmacytoid dendritic cells (PDC) induce innate and adaptive immune responses through production of interferon alpha (IFNa). To date, the role of PDC and IFNa in human immunodeficiency virus 1 (HIV-1) infection remains unclear and even paradoxical. Indeed, HIV-1 disease progression is associated with a decline of PDC, which display reduced ability to produce IFNa when challenged with reference viruses. However, high levels of IFNa in sera of HIV-1 infected individuals are associated with disease progression. Methods: We sought to determine whether disappearance of PDC in HIV-1 disease is due to homing in lymphoid tissues. We also studied steady-state IFNa and myxovirus resistance protein A (MxA) expression, and correlated the results with selected clinical and laboratory parameters. Results: We found a marked decrease of PDC in peripheral blood of HIV-1 infected individuals progressing to disease, but steady PDC counts in lymphoid tissues. Loss of circulating PDC correlated strongly with CD4+ T cell counts. However, PDC from HIV-1 infected individuals progressing to disease expressed IFNa and MxA levels markedly higher than control individuals, although this did not correlate with viremia. Conclusions: Despite selective loss of peripheral PDC during progression to HIV-1 disease, the residual cells express high levels of IFNa, which may contribute to immune suppression. F.ER.5 Natural killer cells and natural killer cell receptors in HIV-1 infection Nattermann J. 1 , Spengler U. 1 , Rockstroh J.K. 1 1 Universitätsklinikum Bonn, Medizinische Klinik und Poliklinik I, Bonn, Germany Natural killer (NK) cells represent a first line of defence against viruses and regulate adaptive immune responses. Recent epidemiologic data indicate that NK cells may have the potential to influence the natural course of HIV-1 infection. NK cell function is regulated by the balance between inhibitory and stimulatory receptors triggered on their cell surface. Inhibitory NK cell receptors (NKR) are specific for MHC class I molecules and comprise two families: the killer-cell immunoglobulin-like receptor (KIR) family and the C-type-lectin family of receptors. Activating receptors such as as NKG2D and the recently discovered natural cytotoxicity receptors (NCRs) NKp30, NKp44 and NKp46 provide the “on signal” for NK cell stimulation during interaction with their target cells. Of note, NK cell receptors are heterogeneously expressed on individual NK cells enabling further phenotypic distinction of NK cell subsets based on the constitutive or inducible expression of the various NK cell receptors. In addition, accessory NK cell receptors (e.g. NKp-80, CD161, CD96 and CD244) can enhance NK cell activation induced by the other receptors. HIV-1 infection is associated with substantial changes in expression of NKR and NKR ligands. Reduced expression of NKp30 and NKp46 in progressive HIV-1 infection has been shown to impair lytic activity of NK cells. However, HIV-1 infection is also associated with an up-regulation of KIR which has been suggested to rendering NK cells more sensitive to virally infected target cells. Expression of the NKR ligands HLA- A and -B is down-regulated in HIV-1 infection. In contrast, expression of the non-classical HLA-E molecule is increased on HIV-1 infected CD4+ lymphocytes. This might be of special relevance as increased HLA-E expression has been shown to impair antibody dependent cytotoxic activity of NK cells, reduce direct lysis of infected CD4+ lymphocytes by NK cells, and affect cytokine secretion of NK cells, which in turn affects NK cell cross-talk with CD8+ T lymphocytes and dendritic cells. Overall, HIV-1 infection is associated with perturbations in the expression of NKR, leading to functional abnormalities of NK cells, which possibly contributes to the impairment of innate host defenses in HIV-infected individuals. F.ER.6 The role of dendritic cells in the blood Schmidt B. 1 1 Virological Institute, Clinical and Molecular Virology, National Reference Centre for Retroviruses, Erlangen, Germany Stem cells differentiate into a common myeloid (CMP) and a common lymphoid precursor (CLP). The CMP develops into the tissue-associated institial dendritic cells (DC), the skin-related Langerhans cells, and the pre-DC1 or myeloid dendritic cells (MDC). The latter are mainly localized in the peripheral blood until they migrate to secondary lymphatic tissue and mature into myeloid DC1 after encounter of their specific antigen. The CLP develops into the pre-DC2 or plasmacytoid dendritic cells (PDC), which are depleted from the peripheral blood to the lymph nodes after stimulation and maturation into lymphoid DC2. Upon stimulation, both DC populations in the blood upregulate the chemokine receptor 7 (CCR7), which binds to the ligands CCL19 and CCL21 expressed on high endothelial venules of lymphatic tissue. The myeloid DC are mainly involved in adaptive immune responses by antigen endocytosis, processing and presentation to naïve T lymphocytes, whereas the lymphoid DC are crucial for innate immune responses. Innate immunity is an evolutionary conserved system which generates a rapid response after recognition of certain molecular patterns, e.g. CpG motifs. In contrast, adaptive immunity is only present in vertebrates and responds to specific epitopes presented in the MHC context. Memory and booster responses are well-known for adaptive, but not innate immunity. In HIV infection, both numbers and function of PDC as well as MDC are reduced. Recent data indicate that both PDC and MDC can be infected by CXCR4-tropic and in particular CCR5-tropic viruses. Thus, they represent a major HIV-1 reservoir and their migration to lymphatic tissue contributes to HIV dissemination. PDC are the main type I interferon (IFN) producing cells in the blood, which upon viral stimulation elicit a Th1-based immune stimulation. IFNs exhibit a strong antiviral capacity in vitro, however the dominant effect in vivo is antiproliferative which prevents a CD4+ cell increase. In addition, IFNs induce an upregulation of CD253 (TRAIL), which enhances the apoptosis of CD4+ cells.
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