Roles of full-length and Δα1 HLA-G isoforms in NK-cell regulation and vascular SARS-CoV-2 infection

Human Leukocyte Antigen-G (HLA-G) is a key immunomodulatory molecule with multiple isoforms, including recently identified variants lacking the α1 domain (HLA-G Δα1). The absence of the α1 domain may reduce immune inhibition, particularly of Natural Killer (NK) cells, which are often suppressed during viral infections such as SARS-CoV-2. This suggests a novel immune regulatory mechanism that could mitigate COVID-19-related complications, including coagulopathies. This study investigates the influence of full-length and Δα1 HLA-G isoforms in NK-cell activity in vitro during SARS-CoV-2 infection and whether their expression associates with viral persistence and coagulopathy in COVID-19 patients, using vascular specimens retrieved from surgical procedures. RCC7 cell lines engineered to express either the full-length or Δα1 form of HLA-G were infected with Omicron SARS-CoV-2 to assess NK cell-mediated cytotoxicity in a co-culture system. Contrary to full-length, Δα1 HLA-G only partially inhibited NK activation, allowing greater cytotoxicity and higher IFN-I/II expression. To evaluate clinical relevance, vascular tissues from coagulopathic COVID-19 patients were analyzed for in situ SARS-CoV-2 persistence and HLA-G isoform expression. SARS-CoV-2 negative tissues more frequently expressed Δα1 and displayed higher systemic interferon (IFNs) levels. Among infection-positive cases, Δα1 expression was also associated with stronger IFN-β and IFN-γ responses. These in vivo trends mirror in vitro findings, supporting a model in which full-length HLA-G dampens NK-mediated clearance of infected vascular cells, favoring viral persistence and potentially contributing to immunothrombosis, while Δα1 permits enhanced antiviral immunity. Overall, these findings identify distinct immunomodulatory roles for HLA-G isoforms in SARS-CoV-2 infection. The Δα1 variant exhibits reduced inhibitory potency, partially preserving NK-cell antiviral functions and modulating interferon responses, whereas full-length HLA-G may facilitate vascular viral persistence and coagulopathy. HLA-G isoform profiling may thus represent a novel biomarker and therapeutic target in COVID-19 associated vascular pathology.