Immunology research update from www.immunopaedia.org.za.
In a new study published in PLOS Pathogens, researchers have demonstrated how specific features on the surface of HIV-infected cells play a key role in immune system evasion (Immunity to HIV). Adeniji, et al., have reported that HIV-infected cells are using a type of sugar molecule, sialic acid, to evade natural killer immune surveillance. In addition, the study has revealed an mechanism that inhibits HIV-infected cells whilst leaving healthy cells unaffected. The authors have identified a novel mechanism, glyco-immune checkpoint interaction, which allows HIV-infected cells to evade immune surveillance. They further developed a novel approach that selectively targets these interactions on the surface of these infected cells in order to inhibit or break these interactions.
Sialic acid is expressed on the surface of HIV-infected cells. These sugars bind to the surface of natural killer (NK) cells. Siglec-9 is an MHC-independent inhibitory receptor expressed on a subset of natural killer cells. Siglec-9 restrains NK cytotoxicity by binding to sialoglycans (sialic acid-containing glycans) on target cells. Siglec-9 functions within their novel identified mechanism as a “glyco-immune negative checkpoint.”
Through the use of in vivo phenotypic analyses, Adeniji identified 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.
The 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 (Figure 2). It is also important to note that Siglec-9+ NK cells exhibit higher cytotoxicity towards HIV-infected cells compared to Siglec-9– NK cells.
In short, the team discovered that the infected cells can take advantage of this inhibitory connection to evade immune surveillance. They then investigated whether they could interfere with this interaction/connection. The researchers identified and developed a sialidase conjugate linked to HIV antibodies (Figure 3) which was an effective approach towards manipulating the interaction. This antibody-sialidase conjugate only targeted sialic acid on HIV cells. This allowed immune cells to target HIV-infected cells while leaving healthy unaffected.
In their own words:
“…our study is the first to describe Siglec-9+ CD56dim NK cells in vivo as an NK subpopulation that can be exploited by HIV-infected cells to evade immunosurveillance. Our study is also the first to describe that this population is highly cytotoxic but is being restrained by the inhibitory marker (Siglec-9) they express (analogous to PD1 expression in highly activated CD8+ T cells). Finally, we developed a proof-of-concept approach (bNAb-sialidase conjugates) to selectively disrupt Siglec-9/sialoglycan interactions between NK cells and HIV-infected cells. This approach represents a promising, novel immunotherapeutic tool to be used in the future (in concert with latency-reversal agents or during ART-cessation) to clear reactivated HIV latently-infected cells.”
Journal Article: Adeniji, et al., 2021. Siglec-9 Defines and Restrains a Natural Killer Subpopulation Highly Cytotoxic to HIV-infected Cells. PLOS pathogens.