Modification of the innate immune response during feline immunodeficiency virus infection
Date
2008
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Abstract
Lentiviruses such as the human immunodeficiency virus (HIV) and the feline immunodeficiency virus (FIV) have successfully evolved to both use and subvert the host innate and adaptive immune responses to establish long-term infections. Investigation into the mechanisms lentiviruses use to overcome host immune response allows the development of potential therapies and elucidates the intricacies of the immune response. Dendritic cells are professional antigen presenting cells that are intricately involved in innate immune responses and in coordinating the adaptive immune response. However, these same cells have been implicated in initial lentiviral infection, transfer of infection to other cells of the immune system, and alteration of the immune response to allow chronic and progressive infection of the host. To better understand the effects of lentiviral infection on myeloid dendritic cells (mDC), we used the FIV model and bone marrow-derived mDC to evaluate differences in growth, phenotype, and function. We found that chronic FIV infection did not affect mDC growth in culture, phenotype, or maturation as assessed by CD11c, MHC class II, CD80, and CD1a and ability to uptake dextran particles. However, mDC from FIV-infected cats were found to have significantly decreased ability to stimulate proliferation of allogeneic CD4+ T cells in the mixed leukocyte reaction. To begin a mechanistic examination of FIV-induced alteration of mDC function, we examined cytokine responses to Toll-like receptor (TLR) ligands and CD40L. We documented changes in the ratio of the immunoregulatory cytokines IL12 and IL10 in response to select TLR ligands and CD40L, which could result in impaired immune responses, impaired T cell interactions, and enhanced viral survival. Having identified alterations in DC function with FIV infection, we attempted to augment the antiviral effects of mDC by supplementing IL-12 levels in vivo using an adenoviral vector. Consistent with the known complexity of the immune response, increased IL12 levels proved toxic and thereby failed to be a viable means of enhancing the innate immune response to lentiviral infection. Our research documents functional changes induced in bone marrow-derived mDC by chronic FIV infection and provides a means of further investigation into the development, mechanisms, and therapies for those changes.
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Subject
bone marrow
dendritic cells
FIV
feline
innate immunity
lentivirus
myeloid
animal sciences
virology
immunology