Early Myeloid Dendritic Cell Dysregulation is Predictive of Disease Progression in Simian Immunodeficiency Virus Infection

Abstract

Myeloid dendritic cells (mDC) are lost from blood in individuals with human immunodeficiency virus (HIV) infection but the mechanism for this loss and its relationship to disease progression are not known. We studied the mDC response in blood and lymph nodes of simian immunodeficiency virus (SIV)-infected rhesus macaques with different disease outcomes. Early changes in blood mDC number were inversely correlated with virus load and reflective of eventual disease outcome, as animals with stable infection that remained disease-free for more than one year had average increases in blood mDC of 200% over preinfection levels at virus set-point, whereas animals that progressed rapidly to AIDS had significant loss of mDC at this time. Short term antiretroviral therapy (ART) transiently reversed mDC loss in progressor animals, whereas discontinuation of ART resulted in a 3.5-fold increase in mDC over preinfection levels only in stable animals, approaching 10-fold in some cases. Progressive SIV infection was associated with increased CCR7 expression on blood mDC and an 8-fold increase in expression of CCL19 mRNA in lymph nodes, consistent with increased mDC recruitment. Paradoxically, lymph node mDC did not accumulate in progressive infection but rather died from caspase-8-dependent apoptosis that was reduced by ART, indicating that increased recruitment is offset by increased death. Lymph node mDC from both stable and progressor animals remained responsive to exogenous stimulation with a TLR7/8 agonist. These data suggest that mDC are mobilized in SIV infection but that an increase in the CCR7-CCL19 chemokine axis associated with high virus burden in progressive infection promotes exodus of activated mDC from blood into lymph nodes where they die from apoptosis. We suggest that inflamed lymph nodes serve as a sink for mDC through recruitment, activation and death that contributes to AIDS pathogenesis.

Author Summary

Myeloid dendritic cells (mDC) are essential innate immune system cells that are lost from blood in human immunodeficiency virus infection through an ill-defined mechanism. We studied the kinetics of the mDC response in blood and lymph nodes of rhesus macaques infected with the closely related simian immunodeficiency virus. We found that differences in the number of blood mDC correlated with eventual disease outcome, as at virus set-point mDC were increased in blood in animals remaining disease free but lost from blood in animals that progressed rapidly to AIDS. mDC loss was linked to an increase in the chemokine axis responsible for mDC recruitment to lymph nodes; however, mDC did not accumulate in tissues but rather died from apoptosis. Lymph node mDC remained responsive to stimulation with a TLR7/8 agonist during infection. Importantly, mDC dysregulation was partially reversed by antiretroviral therapy. These data indicate that chronic mDC recruitment, activation and death within lymph nodes precede development of disease in SIV infected monkeys and may play a role in AIDS pathogenesis.