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CD4 + T cells migrate throughout the body and form immune synapses to carry out their functions. Both of these actions require dynamic actin structures, which are disrupted by HIV proteins. Our study suggests that a key HIV protein, Nef, might disrupt a vital internal cellular machinery that helps immune cells move and function properly. Our microscopic and proteomics studies suggest a new model in which Nef inhibits a large protein complex at the front of migrating T cells. Restoring this cytoskeletal dysfunction may be key to restoring CD4 + T-cell survival and function, which may improve adaptive immune responses during HIV infection.

Objectives Immunisation remains the most cost‐effective mechanism to combat influenza infection and is widely employed against seasonal influenza viruses. Zoonotic transmission of avian influenza A viruses represents a significant threat to human health given the lack of population‐level immunity. Therefore, there is a need to better understand pre‐existing cross‐reactive human immunity against avian influenza strains, as highlighted by the recent global spread of avian H5Nx clade 2.3.4.4b variants. Methods Here, we quantified the frequencies and specificities of B and T cells recognising avian hemagglutinin (HA) within unexposed adults and characterised the ability of seasonal immunisation to boost cross‐reactive immune responses to H5Nx strains, including from clade 2.3.4.4b. Results Low but detectable serum antibody titres against H5 and H7 avian influenza HA were observed in donors. The frequency of memory B cells with cross‐reactive recognition of H5 and H7 HA was below 0.13% and two‐ to five‐fold lower than populations of seasonal HA‐specific B cells. Boosting of B‐cell responses against clade 2.3.4.4b H5Nx HA following seasonal immunisation was sporadic with only three of 19 individuals showing an increased population of probe‐positive cells. Cross‐reactive B cells generally expressed immunoglobulins drawn from variable heavy chain genes associated with HA stem recognition. CD4+ T‐cell responses towards H5 HA were weakly boosted with little increase in circulating T follicular helper cell populations. Conclusion These findings highlight the need for avian influenza‐specific vaccine products to bolster immunity in human populations. Such vaccines could aid pre‐pandemic preparedness by expanding baseline frequencies of avian influenza‐specific memory lymphocytes. In this study, we found low but detectable antibody responses against H5 and H7 avian influenza hemagglutinin in unexposed human cohorts. B‐ and T‐cell responses against these avian‐origin hemagglutinins were poorly boosted by seasonal influenza vaccination.

Understanding the development and maintenance of immunological memory is important for efforts to eliminate parasitic diseases like leishmaniasis. Leishmaniasis encompasses a range of pathologies, resulting from infection with protozoan parasites belonging to the subgenera Leishmania and Viannia of the genus Leishmania. A striking feature of these infections is that natural or drug-mediated cure of infection generally confers life-long protection against disease. The generation of protective T cell responses are necessary to control Leishmania infections. CD4 + T helper (Th) cells orchestrate immune responses in leishmaniasis and IFNγ + Tbet + CD4 + T (Th1) cells are required for the activation of phagocytes to kill captured or resident parasites, while other Th cell subset, including FoxP3 + natural regulatory T cells and Th2 cells can promote disease progression by suppressing the activities of Th1 cells. Upon resolution of a primary Leishmania infection, different subsets of CD4 + T cells, including tissue-resident memory T cells, effector memory T cells, central memory T cells, and short-lived effector T cells, help to confer resistance against reinfection. To maintain long-term protective Leishmania- specific CD4 + T cells responses, it is believed that persistent parasites or re-exposure to parasites at regular intervals is required (concomitant immunity). Despite the advances in our understanding about the immune responses during leishmaniasis, the generation of long-lasting protective immunity via vaccination has yet to be achieved. In this review, we summarize our current understanding about the formation and maintenance of immunological memory and control of leishmaniasis at the individual and population level. We will focus on Indian visceral leishmaniasis and discuss T cell responses that contribute to susceptibility to leishmaniasis, parasite persistence in populations and the environment, as well as describing advances in the development of leishmaniasis vaccines aimed at inducing protective CD4 + T cell responses.

Background Human adenoviruses (HAdVs) frequently cause common respiratory or gastrointestinal infections among children, adults, individuals with immune deficiencies, and other vulnerable populations with varying degree of symptoms, ranging from mild to server, and in some cases, even fatalities. Despite the significant clinical impact of HAdVs, there is currently no approved vaccine available. Methods This study explores the potential of the adenovirus type 5 fiber knob (Ad5-FK) to stimulate the production of Ad-specific neutralizing antibodies and T-cell responses in mice. Based on structure predictions, we first expressed Ad5-FK in E. coli and confirmed the assembly of FK into its trimeric form. After testing the binding capability of the trimeric FK to susceptible cells, the immunogenicity of the protein in combination with the c-di-AMP adjuvant was assessed in BALB/c mice. Results The purified Ad5-FK exhibited self-trimerization and maintained correct conformation akin to the authentic FK structure. This facilitated effective binding to susceptible HEK293 cells. Notably, the protein demonstrated significant inhibition of HEK293 cells infection by rAd5-GFP. Immunization of BALB/c mice with Ad5-FK, or Ad5-FK mixed with c-di-AMP yielded FK-specific antibodies with potent neutralization capacity. Significantly, Ad5-FK was found to elicit a vigorous CD4 + T-cell response in the immunized mice. Conclusion Our findings underscore the efficacy of FK-based vaccine in eliciting anti-Ad humoral immune response and CD4 T-cell immune reactions essential for protection against viral infections.

Human immunodeficiency virus type 1 (HIV) infection substantially increases the risk of developing tuberculosis. There is extensive depletion of Mycobacterium tuberculosis–specific CD4+ T cells in blood during early HIV infection, but little is known about responses in the lungs at this stage. Given that mucosal organs are a principal target for HIV-mediated CD4+ T-cell destruction, we investigated M. tuberculosis–specific responses in bronchoalveolar lavage (BAL) from persons with latent M. tuberculosis infection and untreated HIV coinfection with preserved CD4+ T-cell counts. M. tuberculosis–specific CD4+ T-cell cytokine (interferon γ, tumor necrosis factor α, and interleukin 2) responses were discordant in frequency and function between BAL and blood. Responses in BAL were 15-fold lower in HIV-infected persons as compared to uninfected persons (P = .048), whereas blood responses were 2-fold lower (P = .006). However, an increase in T cells in the airways in HIV-infected persons resulted in the overall number of M. tuberculosis–specific CD4+ T cells in BAL being similar. Our study highlights the important insights gained from studying M. tuberculosis immunity at the site of disease during HIV infection.

Vaccine-induced immunity is essential for controlling the COVID-19 pandemic. Data on humoral and cellular immunogenicity and safety of different SARS-CoV-2 vaccines in patients with autoimmune rheumatic and musculoskeletal diseases (RMDs) are limited. A single center observational study evaluated the immunogenicity and safety of the two-dose regimen of the BBIBP-CorV inactivated, Gam-COVID-Vac and AZD1222 adenovirus-based, and BNT162b2 and mRNA-1273 mRNA-based vaccines in patients with RMDs (n = 89) compared with healthy controls (n = 74). Neutralizing anti-RBD (receptor binding domain) specific antibodies and SARS-CoV-2 specific T-cell response were measured one and four months after the second vaccine dose in parallel with vaccination efficacy and safety. Disease-specific comparison showed that antibody response at four months was higher in spondylarthropathies compared to rheumatoid arthritis and autoimmune RMDs. Risk factors for reduced immunogenicity included longer disease duration, positive immunoserological profile and anti-CD20 therapy of patients. The rate of positive anti-RBD antibody response for healthy controls versus patients after 4 months post vaccination was 69% vs. 55% for the inactivated viral vaccine BBIBP-CorV, 97% vs. 53% for the pooled data of adenovirus vector-based vaccines Gam-COVID-Vac and AZD1222, or 100% vs. 81% for the pooled data of mRNA vaccines BNT162b2 and mRNA-1273, respectively. Patients who received the Gam-COVID-Vac or mRNA-1273 vaccines had a higher proportion of TNF-α producing CD4+ T-cells upon SARS-CoV-2 antigen stimulation compared to the inactivated viral vaccine. All five investigated vaccines were immunogenic in the majority of patients and healthy controls with variable antibody and T-cell response and an acceptable safety profile.

The decrease in CD4 + T cell count is an important cause of poor immune reconstitution in HIV-infected patients. In this study, we analyzed the pyroptosis of T cells in HIV-infected patients with poor immune reestablishment and demonstrated how ENO2, a key enzyme in the glycolytic pathway, affects pyroptosis through mitochondrial ROS. Our results clarified the role of ENO2 in regulating CD4 + T cell pyroptosis in INRs and discussed its possible mechanism. This provides a new target for improving immune reconstitution and intervention in HIV infection.

With the continued spread of human immunodeficiency virus 1 (HIV-1) and its ability to enter and persist within the central nervous system (CNS), concerns have arisen regarding its impact on cognitive health. Indeed, during the early stages of the HIV pandemic, when effective treatments were unavailable, severe neurocognitive impairment was common. Although the widespread use of antiretroviral therapy (ART) has markedly reduced the severity, milder forms of HIV-associated neurocognitive disorders (HAND) remain prevalent. Similar to Alzheimer's disease (AD), elevated amyloid-β (Aβ) accumulation has been observed both intracellularly and extracellularly in the brains of HIV-infected individuals, based on autopsy studies. Aβ is generated through the amyloidogenic processing of amyloid precursor protein (APP), which is abundantly expressed in the brain. While the APP's role in AD pathogenesis has been well established, its broader physiological functions, particularly in the context of viral infections such as HIV-1, remain poorly understood. In the CNS, microglia are crucial for maintaining brain homeostasis and defending against viral infections. HIV-1, however, targets microglia, disrupting their antiviral capacity and contributing to neurotoxicity through multiple mechanisms, such as the release of viral proteins and host-derived neurotoxic factors including proinflammatory cytokines and Aβ. Moreover, HIV-infected microglia can influence neighboring cells such as astrocytes and neurons, further amplifying neurodegenerative processes. This review will focus on recent advances in understanding the antiviral role of APP and its processing during HIV-1 infection, highlighting how APP-mediated defense mechanisms intersect with neurotoxic pathways and the intercellular regulatory networks that link APP to HAND.

Pegylation of biopharmaceuticals is the most common strategy to increase their half-life in the blood and is associated with a reduced immunogenicity. As antigen presentation is a primary event in the activation of CD4 T-cells and initiation of Anti-Drug Antibody (ADA) response, we investigated the role of the PEG molecule on the T-cell reactivity of certolizumab pegol (CZP), a pegylated anti-TNFα Fab. We generated T-cell lines raised against CZP and its non-pegylated form (CZNP) and demonstrated CZP primed few T-cells in comparison to CZNP. CZP-primed lines from 3 donors responded to a total of 5 epitopes, while CZNP-primed lines from 3 donors responded to a total of 7 epitopes, 4 epitopes were recognized by both CZP- and CZNP-primed lines. In line with this difference of T-cell reactivity, CZP is less internalized by the dendritic cells than CZNP. In vitro digestion assay of CZP by Cathepsin B showed a rapid removal of the PEG moiety, suggesting a limited influence of PEG on CZP proteolysis. We therefore demonstrate that pegylation diminishes antigen capture by dendritic cells, peptide presentation to T-cells and T-cell priming. This mechanism might reduce immunogenicity and contribute to the long half-life of CZP and possibly of other pegylated molecules.

•Humoral and cellular immune responses against an inactivated 2009 pandemic H1N1 vaccine.•Hemagglutinin-specific CD4+ T cells could be primed after vaccine inoculation.•Hemagglutinin-specific T-cell responses declined to baseline 6weeks after vaccination.•Virus-specific CD8+ T cells were not elevated throughout vaccination. Influenza A virus remains a major threat to public health, and the inactivated split-virus vaccine is the most prevalent vaccine used worldwide. However, our knowledge about cellular immune responses to the inactivated influenza virus vaccine and its correlation with humoral responses are yet limited, which has restricted our understanding of the vaccine’s protective mechanisms. Herein, in two clinical trials, T-cell responses specific for both previously identified human leucocyte antigen (HLA)-I-restricted epitopes from influenza virus and hemagglutinin (HA) protein were longitudinally investigated before, during, and after a two-dose vaccination with the inactivated 2009 pandemic H1N1 (2009-pH1N1) vaccine. A robust antibody response in all of the donors after vaccination was observed. Though no CD8+ T-cell responses to known epitopes were detected, HA-specific T-cell responses were primed following vaccination, and the responses were found to be mainly CD4+ T-cell dependent. However, HA-specific T-cells circulating in peripheral blood dropped to baseline levels 6weeks after vaccination, but humoral immune responses maintained a high level for 4months post-vaccination. Significant correlations between the magnitude of the HA-specific T-cell responses and hemagglutination inhibition antibody titers were demonstrated, indicating a priming role of HA-specific T-cells for humoral immune responses. In conclusion, our study indicates that HA-specific CD4+ T-cell responses can be primed by the inactivated 2009-pH1N1 vaccine, which may coordinate with the elicitation of antibody protection. These findings would benefit a better understanding of the immune protective mechanisms of the widely used inactivated 2009-pH1N1 vaccine.