Background: Lentivirus infections are characterized by a rapid loss of mucosal CD4+ T cells and breakdown of the gut mucosa. In addition, multiple studies have shown that IFN-α-producing plasmacytoid dendritic cells (pDC) are activated early after lentivirus infection, but despite the importance of the gut mucosae in HIV/SIV pathogenesis, little is known about pDCs in these tissues during acute infection. Methodology: This planned sacrifice study included a total of 21 rhesus macaques – six naive and six infected with SIVmac239 sacrificed at 14 days postinfection, and nine infected with SIVmac239 sacrificed in chronic stage disease. Animals had colorectal and lymph node biopsies prior to infection, were followed longitudinally by blood collection and full tissue collections were performed at necropsy. Phenotypic and functional analyses were performed using polychromatic flow cytometry. Results: During acute SIV infection the frequency of pDCs in blood declined rapidly, as early as day 3 post-infection, with an ~5-fold loss by day 14, inversely correlating with viral load (R = -0.55, p < 0.001). Furthermore, when compared to naive controls, pDC frequencies in animals sacrificed at day 14 post-infection were reduced 5- to 10-fold in lymphoid organs including liver and spleen, but were generally unchanged in lymph nodes. This overall loss in blood and vascular organs coincided with 2- to 8-fold increases in pDCs in colon and jejunum. Of note, when comparing individual animals pDC frequencies in colorectal tissue at day 14 sacrifice were between 6- and 12-fold greater than pre-infection colorectal biopsies. Also, as early as day 6 the gut-homing receptor, α4β7, increased significantly over baseline on circulating pDCs, peaking at ~day 10 post-infection and suggesting a likely mechanism for increased gut-homing. Interestingly, in all chronically infected animals, pDC numbers remained significantly elevated in the mucosa, regardless of viral load. Clinically, re-distribution of pDCs was significantly associated with markers of activation and correlated with loss of CD4+ T cells in the gastrointestinal tract (R = -0.603, p < 0.001), indicating a potential mechanism of pDC-induced depletion. Conclusions: Herein we demonstrate evidence for acute and permanent accumulation of pDCs in the gastrointestinal tract during SIV infection. While pDC accumulation in the mucosa could aid in virus control, over-production of IFN-α derived from these cells could also contribute to increase the immune activation, inflammation, and CD4+ T cell death in the gut mucosa commonly associated with progressive lentivirus infections.
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