Innate Invariant NKT Cell Recognition of HIV-1–Infected Dendritic Cells Is an Early Detection Mechanism Targeted by Viral Immune Evasion

Abstract

Invariant natural killer T (iNKT) cells are innate-like T cells that respond rapidly with a broad range of effector functions upon recognition of glycolipid antigens presented by CD1d. HIV-1 carries Nef- and Vpu-dependent mechanisms to interfere with CD1d surface expression, indirectly suggesting a role for iNKT cells in control of HIV-1 infection. Here, we investigated if iNKT cells can participate in the innate cell-mediated immune response to HIV-1. Infection of dendritic cells (DCs) with Nef- and Vpu-deficient HIV-1 induced upregulation of CD1d in a TLR7-dependent manner. Infection of DCs caused modulation of enzymes in the sphingolipid pathway and enhanced expression of the endogenous glucocylceramide antigen. Importantly, iNKT cells responded specifically to rare DCs productively infected with Nef- and Vpu-defective HIV-1. Transmitted founder viral isolates differed in their CD1d down-regulation capacity, suggesting that diverse strains may be differentially successful in inhibiting this pathway. Furthermore, both iNKT cells and DCs expressing CD1d and HIV-receptors resided in the female genital mucosa, a site where HIV-1 transmission occurs. Together, these findings suggest that innate iNKT cell sensing of HIV-1 infection in DCs is an early immune detection mechanism, which is independent of priming and adaptive recognition of viral antigen, and is actively targeted by Nef- and Vpu-dependent viral immune evasion mechanisms.

Limited immune surveillance in lymphoid tissue by cytolytic CD4+ T cells during health and HIV disease

“…DHIV3 plasmid was provided by Dr. Edward Barker [ 71 ] (Rush University, Chicago, IL). VSV-G pseudotyped viruses were produced as previously described [ 72 ]. PBMCs were stimulated with SEB for 3 days before addition of the pseudotyped virus.…”

The Biology of Monocytes and Dendritic Cells: Contribution to HIV Pathogenesis

“…Immature MDDC exposed to HIV secrete considerable levels of IL-10 leading to resistance of NK-cell mediated lysis and accumulation of poorly immunogenic DC in lymph nodes of HIV-infected individuals [ 232 ]. Innate-like T cells, invariant NKT (iNKT), respond to infected DC as an early immune detection mechanism [ 233 ]; however, the presence of Vpu and Nef inhibit mechanism of action performed by the iNKTs.…”

CD1-Restricted T Cells During Persistent Virus Infections: “Sympathy for the Devil”

“…HIV-1 encodes two proteins, Nef and viral protein U (Vpu) which target numerous immunologically important surface molecules including CD1d ( 265 ). In HIV-1 infected DCs, Vpu neither induces endocytosis nor rapid degradation but suppresses CD1d recycling by retaining CD1d in the early endosome ( 196 , 266 , 267 ). In contrast, Nef increases CD1d internalization and re-localizes CD1d molecules to the TGN ( 196 , 268 , 269 ).…”

“…In HIV-1 infected DCs, Vpu neither induces endocytosis nor rapid degradation but suppresses CD1d recycling by retaining CD1d in the early endosome ( 196 , 266 , 267 ). In contrast, Nef increases CD1d internalization and re-localizes CD1d molecules to the TGN ( 196 , 268 , 269 ). Thus, Vpu and Nef interfere with iNKT cell activation by complementary mechanisms (Figure 2 ).…”

“…Thus, Vpu and Nef interfere with iNKT cell activation by complementary mechanisms (Figure 2 ). As a result, the capacity of HIV-1 infected DCs to stimulate iNKT cells is impaired ( 196 ).…”