Journal of virology 2017 04 19() pii 10.1128/JVI.00439-17
Glycosylation of Env defines pathogenic properties of SIV. We previously demonstrated that pathogenic SIVmac239 and live-attenuated, quintuple deglycosylated Env mutant (Δ5G) target CD4(+) T cells residing in different tissues during acute infection. SIVmac239 and Δ5G preferentially infected distinct CD4(+) T cells in secondary lymphoid organs (SLOs) and within the lamina propria of the small intestine, respectively (C. Sugimoto et al., J Virol 86:9323-9336, 2012). Herein, we studied the host responses relevant to SIV targeting of CXCR3(+)CCR5(+) CD4(+) T cells in SLOs. Genome-wide transcriptome analyses revealed that Th1-polarized inflammatory responses, defined by expression of CXCR3 chemokines, were distinctly induced in the SIVmac239-infected animals. Consistent with a robust expression of CXCL10, CXCR3(+) T cells were depleted from blood in the SIVmac239-infected animals. We also discovered that elevation of CXCL10 expression in blood and SLOs were secondary to the induction of CD14(+)CD16(+) monocytes and MAC387(+) macrophages, respectively. Since the significantly higher levels of SIV infection in SLOs occurred with a massive accumulation of infiltrated MAC387(+) macrophages, T cells, dendritic cells (DCs) and residential macrophages near high endothelial venules, the results highlight critical roles of innate/inflammatory responses in SIVmac239-infection. Restricted infection in SLOs by Δ5G also suggests that glycosylation of Env modulates innate/inflammatory responses elicited by cells of monocyte/macrophage/DCs lineage.IMPORTANCE We previously demonstrated that a pathogenic SIVmac239 and a live-attenuated, deglycosylated mutant Δ5G infected distinct CD4(+) T cell subsets in SLOs and the small intestine, respectively (C. Sugimoto et al., J Virol 86:9323-9336, 2012). Accordingly, infections with SIVmac239, but not with Δ5G, deplete CXCR3(+)CCR5(+)CD4(+) T (Th1) cells during the primary infection, thereby compromising the cellular immune response. Thus, we hypothesized that distinct host responses are elicited by the infections with 2 different viruses. We found that SIVmac239 induced distinctly higher levels of inflammatory-Th1 responses than Δ5G. In particular, SIVmac239 infection elicited a robust expression of CXCL10, a chemokine for CXCR3(+) cells, in CD14(+)CD16(+) monocytes and MAC387(+) macrophages, recently infiltrated in SLOs. In contrast, Δ5G infection elicited only modest inflammatory responses. These results suggest that the glycosylation of Env modulates the inflammatory/Th1 responses through the monocyte/macrophage subsets, and elicits marked differences in SIV infection and clinical outcomes.