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Blocking of integrins significantly inhibits HIV-1 infection of human cervical mucosa immune cells and development of founder populations
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.
Linköping University, Department of Clinical and Experimental Medicine, Obstetrics and gynecology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Gynecology and Obstetrics in Linköping.
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]

Slightly more than half of the HIV-1 infected individuals in the world are women and almost all acquire the infection through sexual intercourse. The initial interaction between HIV-1 and the host occurs at the mucosa site and the most common mode to access the submucosa is through dendritic cells (DCs). In the cervical mucosa, HIV-1 exist both as free and opsonized virions and this might influence initial infection. We used a cervical tissue explant model and both free and opsonized virions to study HIV-1 transmission and how it can be prevented.

We found that complement opsonization significantly enhanced HIV-1 infection of DCs compared to free HIV-1, but this increased infection was not seen for CD4+ T cells. Blocking of α4, β7, and β1 integrins demonstrated significant inhibition of infection of both DCs and CD4+ T cells emigrating from mucosa, independent of the use of free or complement opsonized HIV-1. We found a higher impairment of HIV-1 infection in emigrating DCs for complement opsonized virions compared to free virions when the use of αM/β2 and α4 integrins was blocked.

This study showed that block of integrins decreased the HIV-1 infection of both DCs and CD4+ T cells emigrating from the cervical explant tissues and, remarkably, the establishment of founder populations in these tissues. This indicates that preventing or severely lowering initial infection of the cervical mucosa could avert systemic HIV-1 infection and should be considered for development of microbicides to prevent HIV infection and transmission.

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-72342OAI: oai:DiVA.org:liu-72342DiVA: diva2:459221
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)
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Available from: 2011-11-25 Created: 2011-11-25 Last updated: 2013-06-25

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Tjomsland, VeronicaEllegård, RadaKjölhede, PrebenHinkula, JormaLarsson, Marie

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Tjomsland, VeronicaEllegård, RadaKjölhede, PrebenHinkula, JormaLarsson, Marie
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Molecular VirologyFaculty of Health SciencesDepartment of Clinical and Experimental MedicineObstetrics and gynecologyDepartment of Gynecology and Obstetrics in Linköping
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