Targeting Latently Infected Cells via IFITM1
One of the holy grails in cure research is the discovery of markers that would allow the specific targeting of cells harboring latent HIV. The goal is to be able flag those cells for elimination while sparing their uninfected counterparts. So far, a number of cellular receptors have been identified as being more commonly -- but not exclusively -- expressed on latently infected cells, such as PD-1, LAG-3 and TIGIT. In the new issue of the open access journal JCI Insight, Rui André Saraiva Raposo and colleagues from the laboratory of Doug Nixon at The George Washington University add a new candidate to the mix: interferon-induced transmembrane protein 1 (IFITM1).
IFITM1 belongs to a family of proteins that respond to interferons and are involved in a variety of cellular processes, particularly immunological signaling. IFITM1 has also been implicated as an innate HIV restriction factor. Although not a household name, IFITM1 has attained sufficient celebrity to have its own Wikipedia entry.
Raposo and colleagues hypothesized that expression of IFITM1 might be altered by the presence of HIV in latently infected cells. Studying an in vitro model of HIV latency, they found that IFITM1 expression was increased fourfold in resting latent cells when compared with reactivated cells. Furthermore, significant killing of resting latently infected cells could be achieved with a combination of an anti-IFITM1 antibody and natural killer cells (via the mechanism of antibody dependent cellular cytotoxicity or ADCC).
A preliminary analysis of CD4 T cells sampled from HIV+ individuals on ART revealed a significant increase in IFITM1 expression compared to HIV- donors (2% vs. 0.9%), particularly among central memory CD4 T cells, the subset in which most latent HIV resides. This finding makes an inferential case that IFITM1 expression may be elevated in latently infected CD4 T cells from people on ART, but latently infected cells were not specifically identified and analyzed (their rarity makes such analyses challenging). As observed in the in vitro model, IFITM1-expressing CD4 T cells sampled from HIV+ individuals were sensitive to ADCC in the presence of an anti-IFITM1 antibody and natural killer cells.
The researchers note that the approach could be imperfect and potentially lead to the death of uninfected CD4 T cells, but argue it deserves to be explored:
"We acknowledge that residual IFITM1 expression in non-latently infected cells may lead to the death of bystander cells in the event this strategy translates into an eradication approach in humans. Nonetheless, we believe that an eradication strategy involving IFITM1 in conjugation with immune checkpoint molecules shown to contribute to HIV persistence during ART would be of significant value to effectively target and eliminate latently infected cells in vivo."
Richard Jefferys is the coordinator of the Michael Palm HIV Basic Science, Vaccines & Prevention Project Weblog at the Treatment Action Group (TAG). The original blog post may be viewed here.