Abstract
Siglec-9 is an MHC-independent inhibitory receptor expressed on a subset of natural killer (NK) cells. Siglec-9 restrains NK cytotoxicity by binding to sialoglycans (sialic acid-containing glycans) on target cells. Despite the importance of Siglec-9 interactions in tumor immune evasion, their role as an immune evasion mechanism during HIV infection has not been investigated. Using in vivo phenotypic analyses, we found that Siglec-9+ CD56dim NK cells, during HIV infection, exhibit an activated phenotype with higher expression of activating receptors and markers (NKp30, CD38, CD16, DNAM-1, perforin) and lower expression of the inhibitory receptor NKG2A, compared to Siglec-9- CD56dim NK cells. We also found that levels of Siglec-9+ CD56dim NK cells inversely correlate with viral load during viremic infection and CD4+ T cell-associated HIV DNA during suppressed infection. Using in vitro cytotoxicity assays, we confirmed that Siglec-9+ NK cells exhibit higher cytotoxicity towards HIV-infected cells compared to Siglec-9- NK cells. These data are consistent with the notion that Siglec-9+ NK cells are highly cytotoxic against HIV-infected cells. However, blocking Siglec-9 enhanced NK cells' ability to lyse HIV-infected cells, consistent with the known inhibitory function of the Siglec-9 molecule. Together, these data support a model in which the Siglec-9+ CD56dim NK subpopulation is highly cytotoxic against HIV-infected cells even whilst being restrained by the inhibitory effects of Siglec-9. To harness the cytotoxic capacity of the Siglec-9+ NK subpopulation, which is dampened by Siglec-9, we developed a proof-of-concept approach to selectively disrupt Siglec/sialoglycan interactions between NK and HIV-infected cells. We achieved this goal by conjugating Sialidase to several HIV broadly neutralizing antibodies. These conjugates selectively desialylated HIV-infected cells and enhanced NK cells' capacity to kill them. In summary, we identified a novel, glycan-based interaction that may contribute to HIV-infected cells' ability to evade NK immunosurveillance and developed an approach to break this interaction.
Highlights
The barrier to HIV eradication is the ability of the virus to establish persistent infection in CD4+ T cells and possibly other cell types [1,2,3,4,5,6,7]
We found that the cytotoxicity of the Siglec-9+ CD56dim natural killer (NK) subpopulation against HIV-infected cells is being restrained by the inhibitory nature of the Siglec-9 molecule itself
We found that this Siglec-9+ CD56dim NK subpopulation is highly cytotoxic against HIV-infected cells compared to the Siglec-9- CD56dim NK subpopulation
Summary
The barrier to HIV eradication is the ability of the virus to establish persistent infection in CD4+ T cells and possibly other cell types [1,2,3,4,5,6,7]. One proposed approach to reach this goal is "shock and kill” [9] In this approach, latency reversal agents (LRAs) are administered to reverse HIV latency and induce viral production; reversing latency is only the first step (shock). The second step (kill) requires efficient immune responses to clear reactivated cells. Clinical trials involving LRAs have shown that immune responses of HIV-infected ART-treated individuals cannot clear reactivated reservoirs, suggesting that adjuvant immunotherapy is needed [10,11,12,13,14,15,16]. One potential adjuvant strategy is to enhance the cytotoxicity of natural killer (NK) cells during viral reactivation (achieved by LRAs or by ART-cessation). Developing a strategy to achieve this goal would require a better understanding of the factors that determine NK functions against HIV-infected cells
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