No description available.

<p>Breastfeeding from HIV-infected mothers is one of the major sources of pediatric HIV-1 infection; however, an intervention that promotes exclusive breastfeeding has significantly reduced vertical HIV transmission rates and infant mortality. The mechanisms underlying this phenomenon remain unknown; however, have been closely linked to high levels of innate immune factors in breast milk. Indeed, the level of several innate factors in breast milk correlate with protection and/or have direct anti-viral properties <em>in vitro.</em> The innate immune factor, soluble TLR2 (sTLR2) is found in high concentration in breast milk and has previously been investigated for its anti-bacterial properties; however, its anti-viral properties remain poorly understood. Thus, the research presented in this thesis extended our understanding of sTLR2 by characterizing the mechanisms by which sTLR2 inhibited HIV-induced inflammation and infection. Chapter 2 examined the predominant forms of sTLR2 in breast milk from different women, its cellular source, bioavailability and kinetics postpartum. Functionally, we confirmed sTLR2’s anti-bacterial properties and extended to show, for the first time, that sTLR2 directly inhibited HIV infection <em>in vitro.</em> Chapter 3 documented a potential mechanism of sTLR2’s direct inhibition of HIV infection <em>in vitro</em> and, investigated sTLR2 and TLR2 expression in HIV uninfected compared to HIV infected breast milk and breast milk cells, respectively. Chapter 4 investigated the role of TLR2’s recognition of novel HIV pathogen associated molecular patterns (PAMPs), and whether TLR2 expression increased HIV infection and integration. Taken together, we present novel anti-viral functions of sTLR2 by demonstrating that sTLR2 bound to specific HIV PAMPs, which led to significantly decreased HIV-induced inflammation, co-receptor expression, and HIV infection. Furthermore, we demonstrated, for the first time, that TLR2 recognizes specific HIV PAMPs, which led to significantly increased pro-inflammatory cytokine production, co-receptor expression and HIV infection. Thus, sTLR2 and TLR2 represent innate immune factors that might have preventative and therapeutic applications for both infants and adults in the future.<strong><br /> </strong></p> / Doctor of Philosophy (Medical Science)

Das human pathogene Varicella-Zoster Virus (VZV) gehört zur Familie der Herpesviren und ist weltweit verbreitet. Die Primärinfektion verursacht Varicellen, welche durch einen bläschenartigen Hautausschlag charakterisiert ist. Im Anschluss daran etabliert VZV eine lebenslange Latenz und verursacht nach Reaktivierung Herpes Zoster. Seit 2004 ist der Lebendimpfstoff aus attenuierten Virionen des VZV-Stammes V-Oka in Deutschland empfohlen. Im Gegensatz zur Infektion mit zirkulierenden virulenten VZV Stämmen tritt nach Verimpfung des Vakzin-Stammes V-Oka kein Exanthem auf. Die Haut ist der Hauptreplikationsort von VZV und immunologische Unterschiede zwischen virulentem VZV und dem Vakzin-Stamm treten hier am deutlichsten auf. In der vorliegenden Arbeit konnte eine neue Immunevasionsstrategie virulenter VZV Stämme aufgedeckt werden, welche erklären könnte, wie virulente VZV Stämme frühe antivirale Immunantworten umgehen. In Hautläsionen von Herpes Zoster Patienten konnte eine massive Infiltration von myeloiden inflammatorischen Dendritischen Zellen beobachtet werden. In vitro Studien mit Monozyten abgeleiteten Dendritischen Zellen (DC), welche inflammatorische DC repräsentieren, zeigten, eine signifikant erhöhte Expression von CD1c Molekülen nach Infektion mit dem Vakzin-Stamm, sowie virulentem VZV. Funktionelle Untersuchungen mit intraepithelialen CD1c-restringierten gamma delta T Zellen zeigten, dass DC nach Infektion mit dem Vakzin-Stamm phänotypisch und funktionell reiften und somit die T Zellen zur IFN-gamma Sekretion stimulierten. Im Gegensatz dazu wurde die funktionelle Reifung von DC, die mit virulentem VZV infiziert waren, geblockt. Folglich wurde kein bioaktives IL-12 sezerniert, welches als entscheidendes Cytokin zum Aufbau einer antiviralen T-Helfer 1 Immunantwort beiträgt. Darüber hinaus konnte gezeigt werden, dass virulentes VZV die Signalkaskade des Toll-like Rezeptors 2 (TLR2) in DC inhibiert und somit die IL-12 Produktion verhindert. / Varicella-zoster virus (VZV) which belongs to the family of herpesviruses is restricted to humans and distributed worldwide. Primary infection of VZV causes chickenpox characterized by a disseminated rash. Thereafter, VZV establishes a lifelong latency and can be reactivated to cause herpes zoster. Since 2004 the attenuated strain V-Oka of VZV was licensed for Germany to immunize children against VZV infection. In contrast to infection by circulating virulent VZV strains, vaccination with V-Oka remains asymptomatic. The skin is the major replication site of VZV and immunological differences between virulent VZV and the vaccine should become most apparent within this immune organ. In summary, this study discovered a new immune evasion strategy of virulent VZV strains which might explain how virulent VZV strains overcome innate antiviral responses. A strong infiltration of myeloid-derived inflammatory DCs has been detected in skin lesions of herpes zoster patients. In vitro studies with monocyte-derived dendritic cells (DCs), reflecting inflammatory DCs, showed that they were efficiently infected by both, the vaccine and a virulent VZV strain. Intriguingly, a significant upregulation of CD1c molecules on VZV-infected DCs was observed. Functional investigations using intraepithelial CD1c-restricted gamma delta T cells revealed that DCs infected with the vaccine virus were fully instructed to mature, thereby promoting IFN-gamma secretion of gamma-delta T cells. In striking contrast, DCs infected with virulent VZV strains were efficiently blocked to mature functionally. In detail, they did not secrete bioactive IL-12 which is an instrumental cytokine for generation of antiviral T helper 1 responses. Moreover, virulent VZV blocked Toll-like receptor 2 (TLR2) signaling in DCs thereby preventing production of bioactive IL-12 which in turn inhibited IFN-gamma secretion by gamma-delta T cells.