Deciphering NK cell tactics in HIV-1: TRAIL's multifaceted functionality and KIR2D/HLA-C mediated immune pressure

Abstract

NK cells are critical components of the antiviral immune response, detecting changes in the cell surface composition of infected cells through a diverse receptor repertoire, including highly polymorphic killer cell immunoglobulin-like receptors (KIRs) and conserved effector molecules, shared by every individual. In my investigation, we explored the role of these receptors in the context of HIV-1 infection. Through a large-scale screening approach combined with functional assays, we identified Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) to be associated with NK cell degranulation against HIV-1-infected cells. Exploring TRAIL's mechanisms, we uncovered its multifunctionality, extending beyond its known role in inducing receptor-mediated cytotoxicity. Our findings suggest that direct stimulation of membrane-bound TRAIL, through death receptors, triggers degranulation and IFN-γ release. Additionally, we observed that Decoy Receptor 1 (DcR1) and Osteoprotegerin (OPG) induce degranulation, challenging previous notions of their protective roles in TRAIL-mediated cytotoxicity. Based on these discoveries, we suggest that TRAIL endows a multifaceted role in HIV-1 infection, orchestrating various effector functions beyond its conventional role in apoptosis induction via receptor-mediated pathways. Contrary to the conserved molecule TRAIL, we focused in a separate investigation on the highly polymorphic inhibitory KIR2DL receptors due to emerging evidence of HIV-1's differential modulation of their cognate binding partner, HLA-C. Accumulating evidence indicate that HLA-C/KIR2DL interactions can drive HIV-1-mediated immune evasion and contributes to the intrinsic control of HIV-1 infection. Therefore, we examined the impact of specific KIR/HLA-C binding affinities on NK cell receptor repertoire, phenotypically analyzed NK cells, and sequenced HLA-C-modulating viral protein, Vpu, in 122 viremic, untreated HIV-1+ individuals. Our results revealed a genotype-dependent expansion of KIR2DL1+ NK cells, correlated with increased binding affinities between KIR2DL1 and HLA-C allotypes, suggesting that HIV-1 influences NK cell subset composition in a KIR-dependent manner. Furthermore, we observed a preferential selection of Vpu variants that downregulate HLA-C with higher KIR2DL/HLA-C binding affinities, indicating that HIV-1 evades immune responses based on host genetics. This underscores the ongoing arms race between NK cells and HIV-1, highlighting the sophisticated strategies employed by the virus to evade immune surveillance and the importance of host genetic factors in shaping the immune response to HIV-1 infection.