Natural killer cells and antibody-mediated effects in human immunodeficiency virus infection
Author: Johansson, Susanne
Date: 2010-01-29
Location: Gardaulan, Smittskyddsinstitutet, Nobelsväg 18.
Time: 09.00
Department: Institutionen för mikrobiologi, tumör- och cellbiologi / Department of Microbiology, Tumor and Cell Biology
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thesis.pdf (4.674Mb)
Abstract
The human immunodeficiency virus (HIV-1) effectively avoids immunologic
eradication. Certain characteristics of the virus contribute to this,
including the specific targeting of the body s own defense system, the
ability to hide in the host cell genome and the vast viral variability.
Natural killer (NK) cells are important effectors in resistance to virus
infections and there are indications that NK cells have a role also in
HIV-1 infection. HIV-1 specific antibodies can cause neutralization of
free virions, but also contribute to killing of infected cells through
interaction with effector cells, such as NK cells. In this thesis the
involvement of NK cells in acute and chronic HIV-1 infection has been
studied and novel treatment modalities based on NK cells or antibodies
have been examined. In our mouse model for acute HIV-1 infection, we show
that NK cells have a role, since more infectious virus could be retrieved
from NK cell depleted mice than normal mice after inoculation of spleen
cells infected with a HIV-1/MuLV pseudovirus (paper III). In addition,
frequency of NK cells at the site of injection of infected cells were
increased and the NK cells had a more mature phenotype. These studies are
interesting in relation to previous reports on an enhanced NK cell
activity in acute HIV-1 infection in humans and highlight the importance
of considering activation of NK cells in future treatment modalities
targeted to HIV-1.
One possible therapeutic strategy is activation of NK cells by blocking inhibitory NK cell receptors. The KIR binding antibody, 1-7F9, induced activation of NK cells from HIV-1 infected patients and healthy individuals, and the effect could be associated to KIR genotype of the blood donor (paper I). However, we could not detect increased NK cell recognition of HIV-1 infected compared uninfected autologous T cells. This lack of HIV-1 specific effect may be due to the in vitro system used. Phenotypic and functional differences in NK cells from patients that spontaneously control their disease were compared to NK cells from patients with viremia or healthy individuals, but no striking differences were found (paper I and II). NK cells can specifically kill antibody coated infected target cells in a process called antibody dependent cellular cytotoxicity (ADCC). The antibodies elicited in patients differed in ability to induce Env specific ADCC (paper II). Qualitative differences in HIV-specific ADCC antibody responses may thus contribute to control of disease. For induction of efficient antibody mediated killing, monoclonal antibodies may be chemically coupled to cytotoxic drugs. This treatment modality was examined in our model for acute HIV-1 infection and was found to contribute to eradication of HIV-1/MuLV infected cells in the mouse (paper IV). We conclude, based on our studies in the HIV-1/MuLV mouse model, that NK cell activity in acute HIV-1 infection may contribute to early control of infected cells and that HIV-1 envelope specific antibodies conjugated to drugs may efficiently resolve virus infected cells. In addition the possible differences in ADCC inducing antibodies in controller patients deserve further investigation, as do KIR blockade for the treatment of HIV-1 infection.
One possible therapeutic strategy is activation of NK cells by blocking inhibitory NK cell receptors. The KIR binding antibody, 1-7F9, induced activation of NK cells from HIV-1 infected patients and healthy individuals, and the effect could be associated to KIR genotype of the blood donor (paper I). However, we could not detect increased NK cell recognition of HIV-1 infected compared uninfected autologous T cells. This lack of HIV-1 specific effect may be due to the in vitro system used. Phenotypic and functional differences in NK cells from patients that spontaneously control their disease were compared to NK cells from patients with viremia or healthy individuals, but no striking differences were found (paper I and II). NK cells can specifically kill antibody coated infected target cells in a process called antibody dependent cellular cytotoxicity (ADCC). The antibodies elicited in patients differed in ability to induce Env specific ADCC (paper II). Qualitative differences in HIV-specific ADCC antibody responses may thus contribute to control of disease. For induction of efficient antibody mediated killing, monoclonal antibodies may be chemically coupled to cytotoxic drugs. This treatment modality was examined in our model for acute HIV-1 infection and was found to contribute to eradication of HIV-1/MuLV infected cells in the mouse (paper IV). We conclude, based on our studies in the HIV-1/MuLV mouse model, that NK cell activity in acute HIV-1 infection may contribute to early control of infected cells and that HIV-1 envelope specific antibodies conjugated to drugs may efficiently resolve virus infected cells. In addition the possible differences in ADCC inducing antibodies in controller patients deserve further investigation, as do KIR blockade for the treatment of HIV-1 infection.
List of papers:
I. Susanne Johansson, Bo Hejdeman, Jorma Hinkula, Maria H Johansson, François Romagné, Britta Wahren, Nicolai R Wagtmann, Klas Kärre, Louise Berg. (2009). "NK cell activation by KIR-binding antibody 1-7F9 and response to HIVinfected autologous cells in viremic and controller HIV-infected patients." Clinical Immunology. [Accepted]
Pubmed
View record in Web of Science®
II. Susanne Johansson, Erik Rollman, Amy W Chung, Rob J Center, Bo Hejdeman, Ivan Stratov, Jorma Hinkula, Britta Wahren, Klas Kärre, Stephen Kent, Louise Berg. (1970). "Indications for antibody dependent cellular cytotoxicity in HIV-1 disease control." [Manuscript]
III. Susanne Johansson, Hanna Brauner, Jorma Hinkula, Klas Kärre, Britta Wahren, Louise Berg, Maria H Johansson. (1970). "Role of NK cells in local intraperitoneal HIV-1/MuLV infection." [Manuscript]
IV. Susanne Johansson, David M. Goldenberg, Gary L. Griffiths, Britta Wahren, Jorma Hinkula. (2006). "Elimination of HIV-1 infection by treatment with a doxorubicinconjugated anti-envelope antibody." AIDS 20(15): 1911-5.
Pubmed
View record in Web of Science®
I. Susanne Johansson, Bo Hejdeman, Jorma Hinkula, Maria H Johansson, François Romagné, Britta Wahren, Nicolai R Wagtmann, Klas Kärre, Louise Berg. (2009). "NK cell activation by KIR-binding antibody 1-7F9 and response to HIVinfected autologous cells in viremic and controller HIV-infected patients." Clinical Immunology. [Accepted]
Pubmed
View record in Web of Science®
II. Susanne Johansson, Erik Rollman, Amy W Chung, Rob J Center, Bo Hejdeman, Ivan Stratov, Jorma Hinkula, Britta Wahren, Klas Kärre, Stephen Kent, Louise Berg. (1970). "Indications for antibody dependent cellular cytotoxicity in HIV-1 disease control." [Manuscript]
III. Susanne Johansson, Hanna Brauner, Jorma Hinkula, Klas Kärre, Britta Wahren, Louise Berg, Maria H Johansson. (1970). "Role of NK cells in local intraperitoneal HIV-1/MuLV infection." [Manuscript]
IV. Susanne Johansson, David M. Goldenberg, Gary L. Griffiths, Britta Wahren, Jorma Hinkula. (2006). "Elimination of HIV-1 infection by treatment with a doxorubicinconjugated anti-envelope antibody." AIDS 20(15): 1911-5.
Pubmed
View record in Web of Science®
Issue date: 2010-01-08
Rights:
Publication year: 2010
ISBN: 978-91-7409-719-1
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