Antibody binding and ACE2 binding inhibition is significantly reduced for the Omicron variant compared to all other variants of concern

The rapid emergence of the Omicron variant and its large number of mutations has led to its classification as a variant of concern (VOC) by the WHO. Initial studies on the neutralizing response towards this variant within convalescent and vaccinated individuals have identified substantial reductions. However many of these sample sets used in these studies were either small, uniform in nature, or were compared only to wild-type (WT) or, at most, a few other VOC. Here, we assessed IgG binding, (Angiotensin-Converting Enzyme 2) ACE2 binding inhibition, and antibody binding dynamics for the omicron variant compared to all other VOC and variants of interest (VOI), in a large cohort of infected, vaccinated, and infected and then vaccinated individuals. While omicron was capable of binding to ACE2 efficiently, antibodies elicited by infection or immunization showed reduced IgG binding and ACE2 binding inhibition compared to WT and all VOC. Among vaccinated samples, antibody binding responses towards omicron were only improved following administration of a third dose. Overall, our results identify that omicron can still bind ACE2 while pre-existing antibodies can bind omicron. The extent of the mutations appear to inhibit the development of a neutralizing response, and as a result, omicron remains capable of evading immune control.

Co-Stimulatory Molecules during Immune Control of Epstein Barr Virus Infection

The Epstein Barr virus (EBV) is one of the prominent human tumor viruses, and it is efficiently immune-controlled in most virus carriers. Cytotoxic lymphocytes strongly expand during symptomatic primary EBV infection and in preclinical in vivo models of this tumor virus infection. In these models and patients with primary immunodeficiencies, antibody blockade or deficiencies in certain molecular pathways lead to EBV-associated pathologies. In addition to T, NK, and NKT cell development, as well as their cytotoxic machinery, a set of co-stimulatory and co-inhibitory molecules was found to be required for EBV-specific immune control. The role of CD27/CD70, 4-1BB, SLAMs, NKG2D, CD16A/CD2, CTLA-4, and PD-1 will be discussed in this review. Some of these have just been recently identified as crucial for EBV-specific immune control, and for others, their important functions during protection were characterized in in vivo models of EBV infection and its immune control. These insights into the phenotype of cytotoxic lymphocytes that mediate the near-perfect immune control of EBV-associated malignancies might also guide immunotherapies against other tumors in the future.

mGBP2 engages Galectin-9 and Cytoskeleton-associated Protein 4 for immunity against Toxoplasma gondii

Guanylate binding proteins (GBPs) are large interferon-inducible GTPases, executing essential host defense activities against Toxoplasma gondii, an invasive intracellular apicomplexan protozoan parasite of global importance. T. gondii establishes a parasitophorous vacuole (PV) which shields the parasite from the host's intracellular defense mechanisms. Murine GBPs (mGBPs) recognize T. gondii PVs and assemble into supramolecular mGBP homo- and heterocomplexes that are required for the disruption of the membrane of PVs eventually resulting in the cell-autonomous immune control of vacuole-resident pathogens. We have previously shown that mGBP2 plays an important role in T. gondii immune control. Here, in order to unravel mGBP2 functions, we report Galectin-9 (Gal9) and cytoskeleton-associated protein 4 (Ckap4) as critical mGBP2 interaction partners engaged for immunity to T. gondii. Interestingly, Gal9 and Ckap4 also accumulate and colocalize with mGBP2 at the T. gondii PV. Furthermore, we could prove the requirement of Gal9 and Ckap4 for growth control of T. gondii by CRISPR/Cas9 mediated gene editing. These discoveries clearly indicate that mGBP2 engages Gal9 and Ckap4 and that Gal9 and Ckap4 are critical factors for the mGBP2 coordinated cell autonomous host defense mechanism against T. gondii.

An HLA-I signature favouring KIR-educated Natural Killer cells mediates immune control of HIV in children and contrasts with the HLA-B-restricted CD8+ T-cell-mediated immune control in adults

Natural Killer (NK) cells contribute to HIV control in adults, but HLA-B-mediated T-cell activity has a more substantial impact on disease outcome. However, the HLA-B molecules influencing immune control in adults have less impact on paediatric infection. To investigate the contribution NK cells make to immune control, we studied >300 children living with HIV followed over two decades in South Africa. In children, HLA-B alleles associated with adult protection or disease-susceptibility did not have significant effects, whereas Bw4 (p = 0.003) and low HLA-A expression (p = 0.002) alleles were strongly associated with immunological and viral control. In a comparator adult cohort, Bw4 and HLA-A expression contributions to HIV disease outcome were dwarfed by those of protective and disease-susceptible HLA-B molecules. We next investigated the immunophenotype and effector functions of NK cells in a subset of these children using flow cytometry. Slow progression and better plasma viraemic control were also associated with high frequencies of less terminally differentiated NKG2A+NKp46+CD56dim NK cells strongly responsive to cytokine stimulation and linked with the immunogenetic signature identified. Future studies are indicated to determine whether this signature associated with immune control in early life directly facilitates functional cure in children.

Two distinct mechanisms leading to loss of virological control in the rare group of antiretroviral therapy-naïve, transiently aviraemic children living with HIV

HIV-specific CD8+ T-cells play a central role in immune control of adult HIV, but their contribution in paediatric infection is less well-characterised. Previously, we identified a group of ART-naïve children with persistently undetectable plasma viraemia, termed ‘elite controllers’, and a second group who achieved aviraemia only transiently. To investigate the mechanisms of failure to maintain aviraemia, we characterized in three transient aviraemics (TAs), each of whom expressed the disease-protective HLA-B*81:01, longitudinal HIV-specific T-cell activity and viral sequences. In two TAs, a CD8+ T-cell response targeting the immunodominant epitope TPQDLNTML (‘Gag-TL9’) was associated with viral control, followed by viral rebound and the emergence of escape variants with lower replicative capacity. Both TAs mounted variant-specific responses, but only at low functional avidity, resulting in immunological progression. By contrast, in TA-3, intermittent viraemic episodes followed aviraemia without virus escape or a diminished CD4+ T-cell count. High quality and magnitude of the CD8+ T-cell response was associated with aviraemia. We therefore identify two distinct mechanisms of loss of viral control. In one scenario, CD8+ T-cell responses initially cornered low replicative capacity escape variants, but with insufficient avidity to prevent viraemia and disease progression. In the other, loss of viral control was associated neither with virus escape nor progression, but with a decrease in the quality of the CD8+ T-cell response, followed by recovery of viral control in association with improved antiviral response. These data suggest the potential for a consistently strong and polyfunctional antiviral response to achieve long-term viral control without escape. IMPORTANCE Very early initiation of antiretroviral therapy (ART) in paediatric HIV infection offers a unique opportunity to limit the size and diversity of the viral reservoir. However, only exceptionally is ART alone sufficient to achieve remission. Additional interventions are therefore required that likely include contributions from host immunity. The HIV-specific T-cell response plays a central role in immune control of adult HIV, often mediated through protective alleles such as HLA-B*57/58:01/81:01. However, due to the tolerogenic and type 2 biased immune response in early life, HLA-I-mediated immune suppression of viraemia is seldom observed in children. We describe a rare group of HLA-B*81:01-positive, ART-naïve children who achieved aviraemia, albeit only transiently, and investigate the role of the CD8+ T-cell response in the establishment and loss of viral control. We identify a mechanism by which the HIV-specific response can achieve viraemic control without viral escape, that can be explored in strategies to achieve remission.

Antitumor effect on immune control points (PD-1/PD-L1) in malignant neoplasms

Introduction. Immunotherapy of malignant neoplasms is a dynamically developing field. Diagnostic possibilities in determining the biomarkers of the tumor response to immunotherapy are discussed. The search for new diagnostic «points» of response is being conducted on the basis of detailed studies of carcinogenesis and cellular biological processes in tumor and unchanged tissues. The aim of this work is to highlight one of the promising points of influence of immunotherapy of malignant tumors of various localizations at the present stage (the PD1/PD-L1 signaling pathway), taking into account the available possibilities of application in practice in the Russian Federation. The analysis of the published activity on immunotherapy with immune checkpoint inhibitors in various malignant tumors was carried out. The search for information research sources was conducted in the open systems E-Library, National Library of Medicine (Pubmed), Cochrane Library for the last 10 years. The article analyzes the progress and prospects in the immunotherapy of malignant tumors of various localizations, including the experience of using the PD-1 inhibitor pembrolizumab in the Chelyabinsk Regional Clinical Center of Oncology and Nuclear Medicine. Information on the use of key diagnostic biomarkers for the prognosis and evaluation of the tumor response to this therapy option is highlighted. The prognostic and diagnostic significance of biomarkers already implemented in practice (PD-L1, MSI) is discussed in the scientific press. Successful immunotherapy has been described in the treatment of uterine body cancer, colon cancer, and colorectal cancer. At the same time, the results of the study of the effectiveness of immunotherapy in uveal melanoma are debatable. Conclusion. The effect on the PD1/PD-L1 signaling pathway with the use of immune checkpoint inhibitors (pembrolizumab, atezolizumab, etc.) is one of the promising directions in the treatment of ZNO of various localizations. The determination of a number of biomarkers by immunohistochemical method, by PCR (PD-L1 receptor, MSI) allows us to identify those cases of ZNO, immunotherapy of which can give a positive effect. New approaches are being sought to influence the signaling pathways of immune control points through the development of new combined drugs. And research is also continuing to determine the predictivity of already used biomarkers of the response to immunotherapy.

Modification of EBV-Associated Pathologies and Immune Control by Coinfections

The oncogenic Epstein–Barr virus (EBV) persistently infects more than 95% of the human adult population. Even so it can readily transform human B cells after infection in vitro, it only rarely causes tumors in patients. A substantial proportion of the 1% of all human cancers that are associated with EBV occurs during coinfections, including those with the malaria parasite Plasmodium falciparum, the human immunodeficiency virus (HIV), and the also oncogenic and closely EBV-related Kaposi sarcoma-associated herpesvirus (KSHV). In this review, I will discuss how these infections interact with EBV, modify its immune control, and shape its tumorigenesis. The underlying mechanisms reveal new aspects of EBV-associated pathologies and point toward treatment possibilities for their prevention by the human immune system.

Atypical presentations of superficial dermatophytoses associated with Ruocco’s immunocompromised cutaneous district: A case series

An immunocompromised district is an area of irregular immune control of the skin occurring due to cutaneous damage of any sort conducive to the development of infections, immune reactions, and tumors. Superficial dermatophytoses are one of the most commonly encountered cutaneous infections, which, in some cases, may have various atypical presentations. Herein, we present a series of eleven such cases in which the presentation of a superficial dermatophytosis was altered by the concurrent presence of a different unrelated dermatosis on the same anatomical site.