Natural killer cells and antibody-mediated effects in human immunodeficiency virus infection

Sammanfattning: 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.

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