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Effects of Complement Opsonization of HIV on Dendritic Cells: and Implications for the Immune Response
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Dendritic cells are key players during HIV pathogenesis, and shape both the immediate immune response at the site of infection as well as directing the adaptive immune response against the virus. HIV has developed a plethora of immune evasion mechanisms that hijack dendritic cell functions, suppressing their ability to mount an accurate immune response and exploiting them for efficient viral transfer to target T cells.

To achieve successful replication within dendritic cells without triggering danger signaling, HIV accomplishes a delicate balance where only a low level of transcription can be sustained without triggering antiviral responses that would harm the virus. Here, we describe how the presence of HSV2 coinfection, which is very common in geographic areas with a high HIV prevalence and almost triples the risk of HIV acquisition, alters dendritic cell state to support much higher levels of HIV infection. We found this effect to be mediated by the STING pathway, which is involved in the sensing of DNA in the cell cytosol. STING activation led to an upregulation of factors such as IRF3 and NFkB that can be used for HIV transcription and a degradation of factors that restrict HIV replication.

In addition, we describe how HIV exploits the human complement system, a group of proteins that usually help the human body to identify dangerous pathogens while avoiding reaction towards self. HIV can coat itself, i.e. become opsonized, in complement fragments that are typically only present on the body’s own cells, allowing it to activate signaling pathways that are associated with tolerance. Dendritic cells that come into contact with complement opsonized HIV do not mount danger responses, despite the fact that HIV-derived single stranded RNA triggers the pathogen recognition receptor TLR8. The suppression of danger responses is mediated by activation of complement receptor 3, and leads to an increased infection of the dendritic cell and affects its interactions with other immune cells. There is a lack of recruitment of NK cells to the site of infection, and an inhibition of NK cell killing, which plays an important role in the destruction of HIV-infected cells in vivo. T cells primed by dendritic cells exposed to complement opsonized HIV have a lower ability to develop towards effector phenotype, and have an increased expression of the markers PD1, TIM3 and LAG3 which are associated with T cell dysfunction and exhaustion. In addition, T cells primed by these dendritic cells in the presence of NK cells upregulate markers CD38, CXCR3 and CCR4, which have been linked to an increased susceptibility to HIV infection.

In summary, we add to the current knowledge on HIV immune evasion mechanisms that allow the virus to establish infection, as well as describing mechanisms that govern whether dendritic cells mount danger signaling and an immune response or not.  

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2018. , p. 65
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1640
Keywords [en]
HIV, dendritic cells, complement, innate immune response, TLR signaling, T cell activation, NK cells, inflammation, antiviral response, immune evasion
National Category
Immunology
Identifiers
URN: urn:nbn:se:liu:diva-151665DOI: 10.3384/diss.diva-151665ISBN: 9789176852217 (print)OAI: oai:DiVA.org:liu-151665DiVA, id: diva2:1251946
Public defence
2018-10-26, Berzeliussalen, Campus US, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2018-09-28 Created: 2018-09-28 Last updated: 2019-09-30Bibliographically approved
List of papers
1. Complement Opsonization of HIV-1 Results in Decreased Antiviral and Inflammatory Responses in Immature Dendritic Cells via CR3
Open this publication in new window or tab >>Complement Opsonization of HIV-1 Results in Decreased Antiviral and Inflammatory Responses in Immature Dendritic Cells via CR3
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2014 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 193, no 9, p. 4590-4601Article in journal (Refereed) Published
Abstract [en]

Immature dendritic cells (iDCs) in genital and rectal mucosa may be one of the first cells to come into contact with HIV-1 during sexual transmission of virus. HIV-1 activates the host complement system, which results in opsonization of virus by inactivated complement fragments, for example, iC3b. We investigated antiviral and inflammatory responses induced in human iDCs after exposure to free HIV-1 (F-HIV), complement-opsonized HIV-1 (C-HIV), and complement and Ab-opsonized HIV-1 (CI-HIV). F-HIV gave rise to a significantly higher expression of antiviral factors such as IFN-beta, myxovirus resistance protein A, and IFN-stimulated genes, compared with C-HIV and CI-HIV. Additionally, F-HIV induced inflammatory factors such as IL-1 beta, IL-6, and TNF-alpha, whereas these responses were weakened or absent after C-HIV or CI-HIV exposure. The responses induced by F-HIV were TLR8-dependent with subsequent activation of IFN regulatory factor 1, p38, ERK, PI3K, and NF-kappa B pathways, whereas these responses were not induced by C-HIV, which instead induced activation of IFN regulatory factor 3 and Lyn. This modulation of TLR8 signaling was mediated by complement receptor 3 and led to enhanced infection. The impact that viral hijacking of the complement system has on iDC function could be an important immune evasion mechanism used by HIV-1 to establish infection in the host.

Place, publisher, year, edition, pages
American Association of Immunologists, 2014
National Category
Basic Medicine
Identifiers
urn:nbn:se:liu:diva-112625 (URN)10.4049/jimmunol.1401781 (DOI)000344079500033 ()25252956 (PubMedID)
Note

Funding Agencies|Swedish Research Council; Swedish Physicians against AIDS Research Foundation; Swedish International Development Cooperation Agency; VINNMER for Vinnova; Linkoping University Hospital Research Fund Grant C-ALF; Swedish Society of Medicine; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Swedish Society for Medical Research

Available from: 2014-12-08 Created: 2014-12-05 Last updated: 2018-09-28Bibliographically approved
2. Impaired NK Cell Activation and Chemotaxis toward Dendritic Cells Exposed to Complement-Opsonized HIV-1
Open this publication in new window or tab >>Impaired NK Cell Activation and Chemotaxis toward Dendritic Cells Exposed to Complement-Opsonized HIV-1
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2015 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 195, no 4, p. 1698-1704Article in journal (Refereed) Published
Abstract [en]

Mucosa resident dendritic cells (DCs) may represent one of the first immune cells that HIV-1 encounters during sexual transmission. The virions in body fluids can be opsonized with complement factors because of HIV-mediated triggering of the complement cascade, and this appears to influence numerous aspects of the immune defense targeting the virus. One key attribute of host defense is the ability to attract immune cells to the site of infection. In this study, we investigated whether the opsonization of HIV with complement (C-HIV) or a mixture of complement and Abs (CI-HIV) affected the cytokine and chemokine responses generated by DCs, as well as their ability to attract other immune cells. We found that the expression levels of CXCL8, CXCL10, CCL3, and CCL17 were lowered after exposure to either C-HIV or CI-HIV relative to free HIV (F-HIV). DCs exposed to F-HIV induced higher cell migration, consisting mainly of NK cells, compared with opsonized virus, and the chemotaxis of NK cells was dependent on CCL3 and CXCL10. NK cell exposure to supernatants derived from HIV-exposed DCs showed that F-HIV induced phenotypic activation (e.g., increased levels of TIM3, CD69, and CD25) and effector function (e.g., production of IFN gamma and killing of target cells) in NK cells, whereas C-HIV and CI-HIV did not. The impairment of NK cell recruitment by DCs exposed to complement-opsonized HIV and the lack of NK activation may contribute to the failure of innate immune responses to control HIV at the site of initial mucosa infection.

Place, publisher, year, edition, pages
American Association of Immunologists, 2015
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-121313 (URN)10.4049/jimmunol.1500618 (DOI)000360013200039 ()26157174 (PubMedID)
Note

Funding Agencies|Swedish Research Council; Swedish Physicians against AIDS Research Foundation [AI52731]; Swedish International Development Cooperation Agency/Swedish Agency for Research Cooperation with Developing Countries-Special Assistant; VINNMER for Vinnova; Linkoping University Hospital Research Fund; central regional agreement on medical training and clinical research (CALF) between Ostergotland County Council and Linkoping University; Swedish Society of Medicine; High Impact Research; University of Malaya [UM.C.625/1/HIR/139]

Available from: 2015-09-16 Created: 2015-09-14 Last updated: 2021-12-29
3. Complement-Opsonized HIV-1 Alters Cross Talk Between Dendritic Cells and Natural Killer (NK) Cells to Inhibit NK Killing and to Upregulate PD-1, CXCR3, and CCR4 on T Cells
Open this publication in new window or tab >>Complement-Opsonized HIV-1 Alters Cross Talk Between Dendritic Cells and Natural Killer (NK) Cells to Inhibit NK Killing and to Upregulate PD-1, CXCR3, and CCR4 on T Cells
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2018 (English)In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 9, article id 899Article in journal (Refereed) Published
Abstract [en]

Dendritic cells (DCs), natural killer (NK) cells, and T cells play critical roles during primary HIV-1 exposure at the mucosa, where the viral particles become coated with complement fragments and mucosa-associated antibodies. The microenvironment together with subsequent interactions between these cells and HIV at the mucosal site of infection will determine the quality of immune response that ensues adaptive activation. Here, we investigated how complement and immunoglobulin opsonization influences the responses triggered in DCs and NK cells, how this affects their cross talk, and what T cell phenotypes are induced to expand following the interaction. Our results showed that DCs exposed to complement-opsonized HIV (C-HIV) were less mature and had a poor ability to trigger IFN-driven NK cell activation. In addition, when the DCs were exposed to C-HIV, the cytotolytic potentials of both NK cells and CD8 T cells were markedly suppressed. The expression of PD-1 as well as co-expression of negative immune checkpoints TIM-3 and LAG-3 on PD-1 positive cells were increased on both CD4 as well as CD8 T cells upon interaction with and priming by NK-DC cross talk cultures exposed to C-HIV. In addition, stimulation by NK-DC cross talk cultures exposed to C-HIV led to the upregulation of CD38, CXCR3, and CCR4 on T cells. Together, the immune modulation induced during the presence of complement on viral surfaces is likely to favor HIV establishment, dissemination, and viral pathogenesis.

Place, publisher, year, edition, pages
FRONTIERS MEDIA SA, 2018
Keywords
dendritic cells; natural killer cells; complement; HIV; cross talk; checkpoint inhibitors; CXCR3; CCR4
National Category
Immunology
Identifiers
urn:nbn:se:liu:diva-147922 (URN)10.3389/fimmu.2018.00899 (DOI)000431174300002 ()29760706 (PubMedID)
Note

Funding Agencies|Swedish Research Council; Swedish Physicians against AIDS Research Foundation; VINNMER for Vinnova; Linkoping University Hospital Research Fund; ALF Grants Region Ostergotland; FORSS; CERiA, University of Malaya [UM.C.625/1/HIR/139]

Available from: 2018-05-23 Created: 2018-05-23 Last updated: 2024-01-17

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