Pathogenesis And Therapeutic Potential Of Plasmacytoid Dendritic Cells In Siv/Shiv-Infected Macaques
Advisory Committee Chair
Patricia Fultz
Advisory Committee Members
Vithal Ghanta
Paul Goepfert
Chris Krug
Allan Zajac
Document Type
Dissertation
Date of Award
2007
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Plasmacytoid dendritic cells (pDCs) are among the first responders during acute viral infections and are the primary producers of IFN-α, a cytokine known to inhibit viral replication and to activate natural killer (NK) cells. In HIV patients pDCs are decreased in number, are dysfunctional, and can harbor HIV-1 proviruses. However, since the time of transmission is usually unknown, pDC-virus interactions immediately after exposure to HIV remain unclear. Using the SIV/SHIV-macaque model, we showed that an acute and sustained loss of blood pDCs occurred during SIVmac239 infections, and when compared to those from naïve controls, pDCs were also significantly reduced in lymphoid tissues of animals in end-stage disease. Interestingly, a comparable loss of pDCs was not observed during SHIV-89.6P infections. Based on isolation of proviral DNA from purified pDCs, both viruses appeared to infect pDCs in vivo, and in vitro pDCs responded to both viruses by upregulating the activation marker CD86 and secreting IFN-α. However, the disease courses of the CCR5-using SIVmac239 and CXCR4-using SHIV-89.6P differed, perhaps a consequence of macaque pDCs expressing less CXCR4 than CCR5 on cell surfaces. Since numbers of pDCs are diminished in SIV and HIV disease, and these cells are critical for eliminating pathogens, it was important to identify methods to enhance the numbers and functional activities of pDCs in SIV/SHIV-infected macaques. Following subcutaneous inoculation of macaques with the hematopoietic cytokine, FLT3-ligand iii (FLT3-L), the numbers of pDCs in bone marrow, blood, and lymph nodes increased. Furthermore, FLT3-L administration resulted in activation of pDCs, CD4+ and CD8+ T cells, and NK cells, as well as increased serum levels of IFN-α, IL-12, and TNF-α. Similar to HIV, this study provides evidence for infection and loss of pDCs during SIV infections, thereby contributing to the overall immunosuppression and opportunistic diseases seen in AIDS. However, CD4+ T cell numbers, viral loads, and SIV-specific antibody titers remained stable during and after FLT3-L administration to macaques, suggesting that FLT3-L might be a useful therapeutic modality not only to expand the numbers of functional pDCs in vivo, but also to augment the innate and adaptive immune responses during chronic lentivirus infections.
Recommended Citation
Reeves, R Keith II, "Pathogenesis And Therapeutic Potential Of Plasmacytoid Dendritic Cells In Siv/Shiv-Infected Macaques" (2007). All ETDs from UAB. 3789.
https://digitalcommons.library.uab.edu/etd-collection/3789