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HLA‐G, an important immune‐checkpoint (IC) molecule that exerts inhibitory signalling on immune effector cells, has been suggested to represent a key player in regulating the immune response to Severe Acute Respiratory Syndrome Coronavirus Type 2 (SARS‐CoV‐2). Since specific single‐nucleotide polymorphisms (SNP) in the HLA‐G 3′untranslated region (UTR), which arrange as haplotypes, are crucial for the regulation of HLA‐G expression, we analysed the contribution of these genetic variants as host factors in SARS‐CoV‐2 infection during acute and post‐acute phases. HLA‐G gene polymorphisms in the 3′UTR were investigated by sequencing in an unvaccinated Coronavirus Disease 2019 (COVID‐19) cohort during acute SARS‐CoV‐2 infection (N = 505) and in the post‐acute phase (N = 253). The HLA‐G 3′UTR haplotype known as UTR‐3 (p = 0.002) and the variant rs17875408 (also known as +3422) T variant (p = 0.004) are independent prognostic risk factors for fatal COVID‐19. The +3422T variant (p = 0.006) predicted also the early loss of neutralising SARS‐CoV‐2 antibodies. In addition, the HLA‐G 3′UTR haplotype UTR‐7 (p = 0.023) emerged as an independent prognostic factor for increased susceptibility to Long‐COVID symptoms after SARS‐CoV‐2 infection. Our study highlights that due to the variability of the 3′UTR genetic background, HLA‐G has the potential to contribute to the progression of SARS‐CoV‐2 infection, extending to the development of Long‐COVID symptoms, despite the likely alterations in the microenvironment and associated HLA‐G‐specific regulatory elements over the course of the disease. By spotlighting HLA‐G, the importance of the genetic background of IC and their pivotal role in modulating immune responses during and after COVID‐19 are emphasised. [ABSTRACT FROM AUTHOR]

Understanding tumor resistance to T cell immunotherapies is critical to improve patient outcomes. Our study revealed a role for transcriptional suppression of the tumor-intrinsic HLA class I (HLA-I) antigen processing and presentation machinery (APM) in therapy resistance. Low HLA-I APM mRNA levels in melanoma metastases before immune checkpoint blockade (ICB) correlated with nonresponsiveness to therapy and poor clinical outcome. Patient-derived melanoma cells with silenced HLA-I APM escaped recognition by autologous [CD8.sup.+] T cells. However, targeted activation of the innate immunoreceptor RIG-I initiated de novo HLA-I APM transcription, thereby overcoming T cell resistance. Antigen presentation was restored in interferon-sensitive (IFN-sensitive) but also immunoedited IFN-resistant melanoma models through RIG-I-dependent stimulation of an IFN-independent salvage pathway involving IRF1 and IRF3. Likewise, enhanced HLA-I APM expression was detected in RIG-[I.sup.hi] ([DDX58.sup.hi]) melanoma biopsies, correlating with improved patient survival. Induction of HLA-I APM by RIG-I synergized with antibodies blocking PD-1 and TIGIT inhibitory checkpoints in boosting the antitumor T cell activity of ICB nonresponders. Overall, the herein-identified IFN-independent effect of RIG-I on tumor antigen presentation and T cell recognition proposes innate immunoreceptor targeting as a strategy to overcome intrinsic T cell resistance of IFN-sensitive and IFN-resistant melanomas and improve clinical outcomes in immunotherapy., Introduction Cytotoxic [CD8.sup.+] T cells are critical mediators of clinical responses in tumor immunotherapy, killing cancer cells upon recognition of HLA class I (HLA-I) tumor antigen peptide complexes. Antigen processing [...]

Viruses are by definition fully dependent on the cellular translation machinery, and develop diverse mechanisms to co-opt this machinery for their own benefit. Unlike many viruses, human cytomegalovirus (HCMV) does suppress the host translation machinery, and the extent to which translation machinery contributes to the overall pattern of viral replication and pathogenesis remains elusive. Here, we combine RNA sequencing and ribosomal profiling analyses to systematically address this question. By simultaneously examining the changes in transcription and translation along HCMV infection, we uncover extensive transcriptional control that dominates the response to infection, but also diverse and dynamic translational regulation for subsets of host genes. We were also able to show that, at late time points in infection, translation of viral mRNAs is higher than that of cellular mRNAs. Lastly, integration of our translation measurements with recent measurements of protein abundance enabled comprehensive identification of dozens of host proteins that are targeted for degradation during HCMV infection. Since targeted degradation indicates a strong biological importance, this approach should be applicable for discovering central host functions during viral infection. Our work provides a framework for studying the contribution of transcription, translation and degradation during infection with any virus.

Haploidentical hematopoietic stem cell transplantation (h-HSCT) is a therapeutic option to cure patients affected by hematologic malignancies. The kinetics and the quality of immune-reconstitution (IR) impact the clinical outcome of h-HSCT and limit the onset of life-threatening Human Cytomegalovirus (HCMV) infection/reactivation. Natural Killer (NK) cells are the first lymphocytes that recover after h-HSCT and they can provide rapid innate immune responses against opportunistic pathogens. By performing a longitudinal single-cell analysis of multiparametric flow-cytometry data, we show here that the persistence at high frequencies of CD158b1b2jneg/NKG2Apos/NKG2Cneg/NKp30pos/NKp46pos (KIRneg) NK cells is associated with HCMV infection/reactivation control. These KIRneg NK cells are "unlicensed", and are not terminal-differentiated lymphocytes appearing early during IR and mainly belonging to CD56bright/CD16neg and CD56bright/CD16pos subsets. KIRneg NK cells are enriched in oxidative and glucose metabolism pathways, produce interferon-γ, and are endowed with potent antiviral activity against HCMV ex vivo. Decreased frequencies of KIRneg NK cells early during IR are associated with clinically relevant HCMV replication. Taken together, our findings indicate that the prolonged persistence of KIRneg NK cells after h-HSCT could serve as a biomarker to better predict HCMV infection/reactivation. This phenomenon also paves the way to optimize anti-viral immune responses by enriching post-transplant donor lymphocyte infusions with KIRneg NK cells. [ABSTRACT FROM AUTHOR]

Human cytomegalovirus (HCMV) is a prototypical β-herpesvirus which frequently causes morbidity and mortality in individuals with immature, suppressed, or senescent immunity. HCMV is sensed by various pattern recognition receptors, leading to the secretion of pro-inflammatory cytokines including tumor necrosis factor alpha (TNFα). TNFα binds to two distinct trimeric receptors: TNF receptor (TNFR) 1 and TNFR2, which differ in regard to their expression profiles, affinities for soluble and membrane-bound TNFα, and down-stream signaling pathways. While both TNF receptors engage NFκB signaling, only the nearly ubiquitously expressed TNFR1 exhibits a death domain that mediates TRADD/FADD-dependent caspase activation. Under steady-state conditions, TNFR2 expression is mainly restricted to immune cells where it predominantly submits pro-survival, proliferation-stimulating, and immune-regulatory signals. Based on the observation that HCMV-infected cells show enhanced binding of TNFα, we explored the interplay between HCMV and TNFR2. As expected, uninfected fibroblasts did not show detectable levels of TNFR2 on the surface. Intriguingly, however, HCMV infection increased TNFR2 surface levels of fibroblasts. Using HCMV variants and BACmid-derived clones either harboring or lacking the ULb’ region, an association between TNFR2 upregulation and the presence of the ULb’ genome region became evident. Applying a comprehensive set of ULb’ gene block and single gene deletion mutants, we observed that HCMV mutants in which the non-adjacent genes UL148 or UL148D had been deleted show an impaired ability to upregulate TNFR2, coinciding with an inverse regulation of TACE/ADAM17. [ABSTRACT FROM AUTHOR]