TLR7/9 stimulation by viral RNA is not a major driver of immune activation in pathogenic SIV infection (P6191)

Abstract

Abstract Chronic immune activation is a fundamental component of AIDS pathogenesis but the mechanism responsible for this process is not understood. Emphasis has been placed on plasmacytoid dendritic cells (pDC), given their capacity to produce interferon (IFN)-α in virus infections and the link between persistent IFN-stimulated gene (ISG) expression and immune activation. We used a dual antagonist of TLR7 and 9 to selectively inhibit pDC responses in SIV infection. Administration of TLR7/9 antagonist blocked blood pDC production of IFN-α and TNF-α following SIVmac251 infection of rhesus macaques, but infection alone induced pDC hyporesponsiveness, whereas blood mDC gained the capacity to secrete IFN-α. In lymph nodes pDC were major but not exclusive producers of IFN-α, which was transient, and inhibited by TLR7/9 blockade. In contrast, TNF-α production in SIV-infected lymph nodes derived from macrophages and T cells, was sustained and was not impacted by TLR7/9 blockade. TLR7/9 blockade had no impact on plasma IFN-α production or ISG expression and did not diminish activation and proliferation of CD4+ and CD8+ memory T cells in either blood or lymph node. These experiments reveal that virus-mediated TLR7/9 activation is not a major contributor to immune activation and suggest that other pathways such as persistent TNF-α production may be significant factors in this process.