Biology subjects

Popova, O.

Publications and source records attributed to Popova, O..

5 recordsLinked to original sources

bioRxiv2026

IFI16/AIM2 inflammasomes control Gal-9 and PVR in myeloid cells from PWH and their targeting improves immunotherapy against HIV-1

Chronic inflammation in people with HIV-1 (PWH) is associated with low CD4/CD8 T-cell ratios and inflammasome activation, which may impair monocyte (Mo) and monocyte-derived dendritic cell (MDDC) function and limit the efficacy of myeloid-based immunotherapies. Here, we investigated the role of inflammasome sensors in regulating immune ligands for TIM3 and TIGIT immune checkpoints in Mo and MDDC from PWH and their capacity to activate HIV-1-specific CD8+ T cells. Following TLR stimulation, galectin-9 (Gal-9), PVR and IL-1{beta} were preferentially upregulated in cells from PWH with low CD4/CD8 ratios. IFI16 and AIM2 expression was increased basally or inducible in Mo and co-localized with caspase-1 in these myeloid cells present in lymphoid tissues of HIV-1-infected humanized mice. Si-RNA or small molecule-mediated inhibition of IFI16/AIM2 reduced Gal-9 and PVR expression in MDDC and enhanced their ability to activate polyfunctional HIV-1-specific CD8+ T-cells displaying improved elimination of infected CD4+ T cells in vitro and in vivo. These findings identify IFI16 and AIM2 as key regulators of myeloid dysfunction and therapeutic targets to enhance HIV-1 immunotherapies.

immunology↗

bioRxiv2025

Differential CD8+ T/NK cell-mediated reduction of HIV-1 replication after combination of ART with TIGIT or KLRG1 blockade in humanized mice

Expression of TIGIT and KLRG1 has been associated to an exhausted, dysfunctional state in natural killer (NK) and CD8+ T cells from people with HIV-1 (PWH), limiting the efficacy of immunotherapies aiming at achieving a functional cure of the infection. Antiretroviral therapy (ART) does not completely reverse this immune exhaustion, and its combination with blockade of immune checkpoint receptors such as TIGIT and KLRG1 could be a promising strategy to promote control of viral replication in PWH. However, the impact of targeting these two immune checkpoint receptors has not been evaluated in vivo. In this study, we used a humanized Bone Marrow, Liver and Thymus (hBLT) mouse model of HIV-1 infection to study the impact of ART in combination with aTIGIT or aKLRG1 or a bispecific aTIGIT/aKLRG1 mAbs. Our results indicated that combination of ART with either aTIGIT or aKLRG1 mAbs led to faster reduction of HIV-1 pVL. Furthermore, viral rebound after ART interruption (ATI) was delayed in mice treated with aTIGIT and aKLRG1 mAbs. Histological detection of HIV-1 p24 in the spleen was restricted to the white pulp in the aKLRG1 mAb-treated group, which correlated with higher infiltration of IFN{gamma}+ CD8+ T cells in these histological regions and with increased cytotoxic CD107a+ Granzyme B+ CD8+ T cells in the spleen. In contrast, control of HIV-1 replication induced by the aTIGIT mAb was associated with an increased splenic CD107a+ IFN{gamma}+ NKG2C+ CD57-adaptive NK cells. In contrast, combination of ART with a bispecific aTIGIT/aKLRG1 mAb was unable to efficiently suppress viral replication or delay viral rebound after ATI, potentially by inducing apoptosis of adaptive NKG2C+ NK. Together, these results suggest that combination of ART with individual TIGIT or KLRG1 blockade may be a promising immunotherapy strategy against HIV-1 by eliciting differential immune control mechanisms.

immunology↗

bioRxiv2024

Seroprevalence and cross-reactivity of neutralizing antibodies to six types of adenoviruses

BackgroundThe use of adenoviral vector vaccines is an effective way to induce an antiviral immune response. Most vaccines used worldwide are based on human adenovirus type 5 (Ad5). Pre-existing natural immunity to Ad5 is a limitation to the frequent use of Ad5-based vectors in gene therapy and vaccination. In the present study, we assessed the seroprevalence and cross-reactivity of neutralizing antibodies to six adenovirus types: Ad1, Ad2, Ad5, Ad19, Ad26, and Ad37. MethodsThe study used immunological and virological research methods. Adenovirus vectors encoding the enhanced green fluorescent protein (EGFP) were developed by the N.F. Gamaleya National Research Center for Epidemiology and Microbiology. For seroprevalence and cross-neutralation study we used a panel of sera from 101 volunteers. ResultsThe conducted correlation analysis showed a strong relationship between seropositivity and the geometric mean titer of neutralizing antibodies to adenovirus. An increase in antibody titers indicates the formation of a humoral immune response and population immunity. We determined that there is no cross-reactivity between NtAbs to Ad1, Ad2, Ad5 and Ad26. ConclusionsBased on the presented data, we assume that Ad1 or Ad2 should be considered the most promising alternative candidates for the development of vaccine vectors.

immunology↗

bioRxiv2024

Combined Dendritic Cell And Anti-TIGIT Immunotherapy Potentiate Trail+ Memory NK Cells Against HIV-1 Infected Cells

Natural Killer (NK) cells are promising tools for the development of immunotherapies targeting persistently infected CD4+ T cells to potentially achieve remission in people with HIV-1 (PWH). However, the chronicity of HIV-1 infection limits the functional properties of NK cells, and additional approaches are needed to potentiate their cytotoxic activity against HIV-1-infected cells. In the present study, we analyzed the reinvigoration of functional NK cells from PWH after priming with autologous dendritic cells (DC) stimulated with nanoparticles containing Poly I:C (Nano-PIC). We show that improved natural cytotoxic function in NK cell from PWH associates with increased proportions of NKG2C+CD57- precursors of memory NK, which eliminate HIV-1 infected CD4+ T cells mainly through the TRAIL receptor. In addition, expression of TIGIT but not TIM3 limited increase in NKG2C+ memory NK cell precursors and associated with persistent dysfunctionality of NK cells after stimulation with Nano PIC-DC. Blockade of TIGIT restored functional capacities of NK cell from PWH eliminating HIV-1 infected cells in vitro. Moreover, combining of NK cell and Nano-PIC-DC with anti-TIGIT mAbs immunotherapy limited the expansion of HIV-1 infected cells in humanized immunodeficient NSG mice transplanted with CD4+ T cells from PWH in vivo. Such viral control was associated with preserved NKG2C memory NK cell precursors, increased expression of granzyme B and TRAIL on NK in tissue from transplanted NSG mice. Together, combination of Nano-PIC DC and anti-TIGIT antibodies may be a promising strategy to increase the efficacy of immunotherapies aimed at HIV-1 cure. One sentence summaryStimulation of memory NK with a combination of DC and anti-TIGIT antibodies increase their ability to eliminate HIV-1 infected CD4+ T cells in vitro and in vivo.

immunology↗

bioRxiv2022

Cross-reactive single-domain antibodies to hemagglutinin stem region protect mice from group 1 influenza A virus infection

The continued evolution of influenza viruses reduces the effectiveness of vaccination and antiviral drugs. The identification of novel and universal agents for influenza prophylaxis and treatment is an urgent need. We have previously described two potent single-domain antibodies (VHH), G2.3 and H1.2, which efficiently neutralize H1N1 and H5N2 influenza viruses in vivo. In this study, we modified these VHHs with Fc-fragment to enhance their antiviral activity. Reformatting of G2.3 into bivalent Fc-fusion molecule increased its in vitro neutralizing activity against H1N1 and H2N3 viruses up to 20-fold and, moreover, resulted in obtaining the ability to neutralize H5N2 and H9N2 subtypes. We demonstrated that a dose as low as 0.6 mg/kg of G2.3-Fc or H1.2-Fc administered systemically or locally before infection could protect mice from lethal challenges with both H1N1 and H5N2 viruses. Furthermore, G2.3-Fc reduced the lung viral load to an undetectable level. Both VHH-Fc showed in vivo therapeutic efficacy when delivered via systemic or local route. The findings support G2.3-Fc as a potential therapeutic agent for both prophylaxis and therapy of Group 1 influenza A infection.

immunology↗