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Complement opsonization of HIV-1 results in a different intracellular processing pattern and efficiency leading to an enhanced MHC I presentation by dendritic cells
Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
National Laboratory for HIV Immunology, Public health Agency of Canada, 1015 Arlington Street Winnipeg, Manitoba, Canada.
Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
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2011 (English)Manuscript (preprint) (Other academic)
Abstract [en]

The antigen processing and presentation processes occurring in dendritic cells (DCs) required for induction of HIV-1 specific T cell responses, which are essential for controlling the viral infection in vivo. The initial interactions of DCs with free HIV-1 (FHIV), or complement opsonized HIV-1 (C-HIV) might influence the routing and nature of pathways used for MHC class I and II restricted presentation. We have examined FHIV, C-HIV, and complement and antibody opsonized HIV-1 (C-IgG-HIV) effects on immature DCs (IDCs) and mature DCs (MDCs) antigen proteolysis, MHC class I and II antigen presentation, and the role of endocytic receptors in presentation of antigens derived from HIV-1. We found that opsonized virions promoted MHC class I presentation by both IDCs and MDCs compared to F-HIV. Indicative of that complement opsonization routes more virions towards the MHC class I presentation pathway. We found that blocking macrophage mannose receptor (MMR) rerouted the HIV-1 to a path leading to higher levels of MHC class I and II presentation. Furthermore, the blocking of β7-integrin also gave an enhanced MHC class I and II presentation by both IDCs and MDCs, whereas the block of αMβ2 integrins, i.e. complement receptor 3 (CR3), decreased the MHC class I and II presentation. In addition, we found that IDCs and MDCs proteolytic activities were modulated by the HIV-1 exposure, for example C-HIV induced an increased proteasome activity in IDCs. Taken together, these findings indicated that endocytic receptors, such as MMR, CR3, and β7 integrin, can promote or disfavor antigen presentation by routing HIV-1 into different endosomal compartments with distinct properties and efficiencies for degradation of viral antigens and MHC class I and II presentation and that HIV-1 affects the antigen processing machineries.

Place, publisher, year, edition, pages
2011.
Keyword [en]
Dendritic cells, complement opsonized HIV-1, antigen presentation
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-72341OAI: oai:DiVA.org:liu-72341DiVA: diva2:459220
Note
|Available from: 2011-11-25 Created: 2011-11-25 Last updated: 2011-11-25Bibliographically approved
In thesis
1. Complement activation - good or evil in HIV-1 infection?: interaction of free and complement opsonized HIV-1 with monocyte derived dendritic cells and immune cells in the cervical mucosa
Open this publication in new window or tab >>Complement activation - good or evil in HIV-1 infection?: interaction of free and complement opsonized HIV-1 with monocyte derived dendritic cells and immune cells in the cervical mucosa
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Worldwide, the heterosexual route is the most common mode of sexual transmission of HIV-1 and women are particularly susceptible to this infection. After penetration of the mucosal epithelium HIV-1 interacts with potential target cells, i.e. dendritic cells (DCs) and CD4+ T cells. The complement system, a key component of the innate immune system, is immediately activated by HIV-1 in vivo. However, HIV-1 can resist complement mediated lysis and become coated with complement fragments and this opsonization influences the viral interaction with immune cells. The DCs are the most potent antigen presenting cell. This cell effectively links the innate recognition of viruses to the generation of an adaptive immune response. However, HIV-1 exploits the function of the DCs to facilitate viral spread and infection. HIV-1 interacts with a range of receptors expressed by the DCs including C-type lectins, integrins and complement receptors (CRs). The uptake of virions by DCs leads to their activation and migration to the lymph nodes. At this site DCs present HIV-1 derived antigen on MHC class I and II molecules and trigger an HIV-1 specific T cell response. The interplay between the virus and the DCs is complex and the initial receptor binding may affect antigen uptake, infection, and antigen presentation.

The fundamental questions of this thesis are the following: How is free and opsonized HIV-1 internalized, processed, and presented on MHC class I and II molecules by DCs and how do free and opsonized HIV-1 particles interact with immune cells in the cervical mucosa?

Our results indicate that opsonization of HIV-1 plays a critical role in the interaction with immune cells. Complement opsonization of HIV-1 (C-HIV) significantly enhanced the internalization by the DCs compared to free HIV (F-HIV). Both C-HIV and F-HIV interacted with the CD4 receptor, C-type lectins and integrins. In addition, opsonization of HIV-1 favored an MHC class I presentation by DCs compared to F-HIV. However, the endocytic receptors macrophage mannose receptor, β7 integrin, and CR3 guided the antigens to different compartments with distinct properties and efficiencies for degradation and MHC class I and II presentation of viral antigens. MHC class I presentation of F-HIV and C-HIV was dependent of viral fusion in a CD4/coreceptor dependent manner. Moreover, MHC class II presentation of antigens derived from HIV-1 required endocytosis and proteolysis in acidified compartments. HIV-1 infection of cervical mucosa immune cells and tissue was assessed in a cervical tissue explant model. C-HIV significantly enhanced infection of DCs compared to F-HIV, whereas C-HIV decreased the infection of CD4+ T cells. Blocking the viral use of integrins in the cervical tissue explants significantly decreased the HIV-1 infection of both emigrating DCs and CD4+ T cells and the establishment of founder populations in these tissues. This thesis work has brought forward new facts that can be used to facilitate the development of an effective vaccine or microbicide.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2011. 68 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1281
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-72343 (URN)978-91-7393-010-9 (ISBN)
Public defence
2011-12-16, Linden, Ing. 65, plan 9, Campus US, Linköpings universitet, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2011-11-25 Created: 2011-11-25 Last updated: 2013-06-25

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Tjomsland, VeronicaEllegård, RadaHinkula, JormaLarsson, Marie

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Tjomsland, VeronicaEllegård, RadaHinkula, JormaLarsson, Marie
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