Lymph nodes (LN) and intestine are the major HIV reservoirs. During SIVagm infection in African Green Monkeys (AGM), NK cells express CXCR5 and migrate into B cell follicles (BCF) of peripheral LN (pLN) where they efficiently control SIVagm replication. In the intestine, SIVagm replicates at high levels but this does not lead to bacterial translocation and chronic inflammation. IgA are important for the control of bacterial translocation and inflammation in the gut. In this study, we aimed at investigating whether there is a link between NK cell-mediated viral control in BCF and intestinal inflammation control via maintenance of IgA production.
AGM and cynomolgus macaques (MAC) were infected with SIVagm.sab92018 and SIVmac251, respectively. We collected blood, mesenteric LN (mLN), jejunum, ileum and colon from each animal before infection, at day 9p.i. and during chronic infection. B, T and NK cell analyses were performed by fluorescence microscopy and/or flow cytometry. Immunoglobulins were isolated by affinity chromatography and quantified by ELISA. To determine IgA/IgG ratios and gp140 antibody specificity, trimeric SIVagm and SIVmac gp140-foldon Env proteins and an IgA-specific probe were produced. Soluble markers of microbial translation and inflammation (i.e. sCD14) were quantified in plasma by ELISA.
NK cells migrated into BCF of mLN during acute SIVagm infection. CXCR5+NK cells showed a negative correlation (p=0.0004; r2=0.66) in LN with follicular Th1 cells, a population responsible of hypergammaglobulinemia. In AGM, intestinal IgA levels (jejunum, ileum and colon) were comparable between acutely infected (mean=0.51-0.45AU), chronically infected (mean=0.53-0.39AU) and non-infected animals (mean=0.49-0.4AU). In acute SIVmac infection, intestinal IgA levels (mean=0.5-0.47AU) were similar to those of uninfected MAC (mean=0.54-0.42AU), but strongly decreased in chronically infected animals (mean=0.12-0.05AU). Similarly, IgA were decreased in BCF of chronically infected MAC. There was a negative correlation between sCD14 and IgA levels in MAC (p= 0.0037; r2=0.32) and not in AGM (p= 0.72; r2=0.012).
Our data unraveled a negative correlation between gut IgA titres and inflammation in SIVmac infection, with a dramatic loss of intestinal IgA in SIV-infected MAC while IgA levels in chronic SIVagm infection remain stable. Hence, we propose that the viral control in BCF could help maintaining normal IgA responses and a better control of gut inflammation.