Newcastle disease virus is one of the most highly contagious infections impacting poultry industries worldwide. This study aimed to develop a bacteriophage display system as a cost-effective and immunogenic method for expressing the immunodominant region of the Newcastle Disease Virus Fusion (F) protein for use in serological assays. Both in-silico and in-vitro analyses indicated that the selected antigen is stable, accurate, and reliable for further in-vivo studies. The displayed antigen successfully detected NDV-GVII-specific antibodies in vaccinated chickens. Additionally, a significant correlation was observed between ELISA and HI test results on chicken serum samples. This approach addresses safety concerns associated with wild-type virulent NDVs and offers improved diagnostic accuracy and scalability, aligning with industry needs for improved Newcastle disease detection, control, and management on poultry farms.

Subunit vaccines offer safety and precision but require adjuvants to overcome weak immunogenicity, particularly for the induction of cellular immunity. Herein, we develop a manganese pyrophosphate mineralized DNA bi-adjuvant-based subunit vaccine platform via biomineralization, which demonstrated the capability to elicit robust antigen-specific cellular immune responses. The Mn/CpG bi-adjuvant modulated the balance between Th1 and Th2 immune responses. More importantly, the synergistic activation of Toll-like receptor 9-like (TLR9) signaling pathways by CpG and cGAS-STING pathways mediated by Mn(II) ions robustly enhanced cellular immunity, which was a magnitude of enhancement over commercial aluminum-based adjuvants both in vitro and in vivo. Furthermore, the mechanistic studies revealed that the Mn(II)-based nanoadjuvant effectively promoted Th1-biased cellular immune response, as evidenced by an elevated IgG2a/IgG1 ratio and enhanced Th1-associated cytokine secretion, alongside a potential reduction in regulatory T cell activity. These insights established critical design principles essential for the development of next-generation manganese-derived adjuvant systems, thereby advancing the frontiers of vaccinology and immunology.

Abstract Oncolytic viruses are most commonly administered via intratumoral injection; however, their clinical efficacy in achieving tumor eradication remains limited by several challenges, including insufficient penetration into all tumor cells and the inability to elicit robust systemic antitumor immune responses capable of eliminating metastatic microtumors. Here, we report an oncolytic adenovirus, OAd-2B6, with an engineered adenoviral E1 region for tumor selectivity and carrying the prodrug- activating enzyme cytochrome P450 2B6 (CYP2B6) to activate the anticancer prodrug cyclophosphamide (Cytoxan, CTX). OAd-2B6 alone induced dose-dependent tumor cell killing across multiple human tumor cell lines and exhibited strong synergistic antitumor effects when combined with CTX. Importantly, OAd-2B6-mediated local activation of CTX resulted in a potent bystander killing effect that eliminated tumor cells not directly infected by the virus. In a H1299 lung cancer xenograft nude mouse model, intratumoral injection of OAd-2B6 combined with CTX significantly inhibited tumor growth and even achieved complete tumor regression, with markedly superior efficacy compared with monotherapy. In immunocompetent mice bearing 4T1 breast cancer xenografts, OAd-2B6 alone inhibited tumor growth and was accompanied by upregulation of IFN-γ and GzmB expression in the tumor-infiltrated T cells. CTX combination therapy further enhances this anti-tumor immune response, promoting the activation of T cells to suppress non-injected tumors at a distal site. Collectively, this study demonstrates that OAd-2B6 exerts potent antitumor effects through multiple mechanisms, including direct oncolysis, intratumoral prodrug activation leading to bystander killing, and enhancement of systemic antitumor immunity. These findings provide a promising strategy for improving the therapeutic efficacy of oncolytic therapy.

Influenza A viruses (IAVs) are significant respiratory pathogens characterized by high mutation rates and frequent genetic reassortments, underscoring the need for vaccines that can induce robust and broadly protective mucosal immunity. While replication-competent vesicular stomatitis virus (VSV) vectors have the potential to elicit mucosal immunity, their neurovirulence raises significant safety concerns. Herein, we report that a semi-replicating VSV (srVSV) vector, composed of one VSV with the glycoprotein (G) gene deleted (rVSVΔG) and another with the L gene deleted (rVSVΔL), has improved safety. Using srVSV, we constructed a monovalent vaccine (srVSV-N1), expressing the neuraminidase 1 (N1) of IAV. A single intranasal dose of srVSV-N1 elicited both systemic and mucosal immune responses against N1, and provided sterilizing immunity against homologous influenza virus. We further generated a bivalent IAV vaccine (srVSV-N1/N2), co-expressing N1 and N2. A single intranasal dose of srVSV-N1/N2 conferred 80% protection against heterologous IAVs (H1N1 and H3N2). Notably, low-dose priming immunization followed by a high-dose boost with srVSV-N1/N2 fully protected mice against lethal heterologous IAV challenges. These findings demonstrate the potential of the srVSV platform for developing mucosal vaccines against IAVs and other respiratory viruses.

SARS-CoV-2 continuously accumulates mutations in the spike receptor-binding domain (RBD), affecting both viral infectivity and antibody evasion. Systematic characterization of RBD mutations is therefore essential for understanding viral adaptation under immune pressure and predicting evolutionary trajectories. In this study, we employed a two-step, non-replicating pseudovirus deep mutational scanning (DMS) platform to measure the effects of all single amino acid substitutions in the RBD of Omicron variant JN.1 and its descendant lineage XEC within a full-length spike background. To identify representative antibodies for escape profiling, we first evaluated six RBD-targeting monoclonal antibodies against JN.1 and XEC pseudoviruses. Only BD55-1205 and 719-14 sIgA retained substantial neutralizing activity and were selected for subsequent escape mapping. The results showed that most single RBD amino acid mutations did not significantly enhance pseudovirus cellular invasion. Among mutations that are functionally retaining and confer marked escape from either antibody, most high escape substitutions cluster within the receptor-binding motif (RBM) and receptor-binding ridge. Furthermore, BD55-1205 and 719-14 sIgA each exhibited distinct, antibody-specific escape sites, demonstrating that different epitope preferences exert unique selective pressures within the same viral lineage. Overall, this pseudovirus-based DMS analysis elucidates the molecular mechanisms of immune escape and fitness for the JN.1 and XEC lineages. Our findings provide critical insights for forecasting SARS-CoV-2 evolution under population immunity and offer guidance for assessing emerging variants, selecting vaccine strains, and optimizing therapeutic antibodies.

Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is a potentially severe autoimmune encephalitis that may rapidly progress to critical illness. We report a young patient with severe anti-NMDAR encephalitis complicated by seizures, psychiatric symptoms, behavioral disturbance, dyskinesia, and dysautonomia. Despite first-line immunotherapy with intravenous methylprednisolone and intravenous immunoglobulin, the patient remained severely disabled. Peripheral blood analysis showed elevated C5a and soluble C5b-9 levels, suggesting activation of the terminal complement pathway. After treatment with eculizumab, a monoclonal antibody targeting complement component C5, seizure ceased and psychiatric symptoms improved rapidly. These findings suggest that complement inhibition may facilitate rapid neurological recovery and may represent a potential therapeutic strategy for selected patients with severe anti-NMDAR encephalitis.

R1-32-like public antibodies, characterized by shared IGHV1-69/IGLV1-40 usage and non-ACE2-competing, spike-destroying activity, are elicited in more than 50% of individuals with COVID-19 and have been implicated in driving recurrent mutations at L452SARS2 and F490SARS2 within their convergent epitope in the SARS-CoV-2 spike receptor-binding domain. These mutations effectively mediate escape from non-affinity-matured R1-32-like antibodies with germline-like sequences. Here, we characterize four affinity-matured R1-32-like antibodies, C092, C807, BD56-104, and BD56-597, with the ability to tolerate L452SARS2 and F490SARS2 mutations. We show that this tolerance arises from residues introduced by somatic hypermutation at convergent positions across multiple CDR loops and surrounding regions, thereby creating additional contacts that reinforce epitope binding. An unusual N354SARS2 glycosylation site, which emerged in BA.2.86 and became fixed in its descendants, is linked to escape from affinity-matured R1-32-like antibodies, implying ongoing selection by this public antibody class. Using an AI model trained on integrated structural, neutralization, and binding data, we further identified ZL525, an ultrapotent R1-32-like antibody with pan-SARS-CoV-2 variant activity, including against the highly evasive KP.3 variant carrying the N354SARS2 glycosylation, and broad sarbecovirus cross-reactivity extending to SARS-CoV-1. Together, these findings highlight how public antibodies shape SARS-CoV-2 antigenic evolution and demonstrate the power of AI-empowered strategies for discovering broadly neutralizing antibodies. ### Competing Interest Statement The authors have declared no competing interest. National Key R&D Program of China, 2021YFA1300903 National Natural Science Foundation of China, 82341085, 32570199, 82495200, 82495203 Emergency Key Program of Guangzhou Laboratory, EKPG21-06 Major Project of Guangzhou National Laboratory, SRPG22-002, EKPG21-30-2 Guangdong Basic and Applied Basic Research Foundation, 2021A1515011289 Science and Technology Planning Project of Guangdong Province, 2023B1212060050, 2023B1212120009 Basic Research Project of Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, GIBHBRP24-02 111 Project, D18010 Natural Science Fund of Guangdong Province, 2025A1515011245 Young Doctoral Starting Sail Project of the Guangzhou Municipal Science and Technology Bureau, 2024A04J4195

BackgroundAlthough immunoglobulin (Ig) alleles play a pivotal role in the antibody response to pathogens, research to understand their role in the humoral immune response is still limited.MethodsWe retrieved the germline sequences for the IGHV from the IMGT database to illustrate the amino acid polymorphism present within germline sequences of IGHV genes. We aassembled the sequences of IgM and IgD repertoire from 130 people to investigate the genetic variations in the population. A dataset comprising 10,643 SARS-CoV-2 spike-specific antibodies, obtained from COV-AbDab, was compiled to assess the impact of SARS-CoV-2 infection on allelic gene utilization. Binding affinity and neutralizing activity were determined using bio-layer interferometry and pseudovirus neutralization assays. Primary docking was performed using ZDOCK (3.0.2) to generate the initial conformation of the antigen-antibody complex, followed by simulations of the complete conformations using Rosetta SnugDock software. The original and simulated structural conformations were visualized and presented using ChimeraX (v1.5).ResultsWe present an allelic atlas of immunoglobulin heavy chain (IgH) variable regions, illustrating the diversity of allelic variants across 33 IGHV family germline sequences by sequencing the IgH repertoire of in the population. Our comprehensive analysis of SARS-CoV-2 spike-specific antibodies revealed the preferential use of specific Ig alleles among these antibodies. We observed an association between Ig alleles and antibody binding epitopes. Different allelic genotypes binding to the same RBD epitope on the spike show different neutralizing potency and breadth. We found that antibodies carrying the IGHV1-69*02 allele tended to bind to the RBD E2.2 epitope. The antibodies carrying G50 and L55 amino acid residues exhibit potential enhancements in binding affinity and neutralizing potency to SARS-CoV-2 variants containing the L452R mutation on RBD, whereas R50 and F55 amino acid residues tend to have reduced binding affinity and neutralizing potency. IGHV2-5*02 antibodies using the D56 allele bind to the RBD D2 epitope with greater binding and neutralizing potency due to the interaction between D56 on HCDR2 and K444 on RBD of most Omicron subvariants. In contrast, IGHV2-5*01 antibodies using the N56 allele show increased binding resistance to the K444T mutation on RBD.DiscussionThis study provides valuable insights into humoral immune responses from the perspective of Ig alleles and population genetics. These findings underscore the importance of Ig alleles in vaccine design and therapeutic antibody development.

Human adenovirus types 55, 11, and 14 (HAdV-55, -11, and -14) are pathogenic respiratory viruses for which no drugs or vaccines are currently available. We report the generation of a replication-incompetent rAd55-5E4 with deleted E1 and E3 genes, which only replicates in cells that provide E1 proteins in trans. In mice and non-human primates, vaccination with live non-replicating rAd55-5E4 elicited robust and durable neutralizing antibody (nAb) and cell-mediated immune responses against HAdV-55, as well as cross-reactivity against HAdV-11 and HAdV-14. Furthermore, vaccination with the live non-replicating rAd55-5E4 elicited much stronger immune responses than inactivated rAd55-5E4. In transgenic mice that express human desmoglein-2, the cellular receptor for HAdV-55, -11 and -14, vaccination with rAd55-5E4 or passive transfer of macaque immune sera collected at 66 weeks post vaccination effectively protected against challenges with HAdV-55, HAdV-11, and HAdV-14. Epitope profiling revealed that nAbs mainly recognize epitopes on hexon hypervariable regions 1, 2, 5, and 7, as well as the fiber knob. This study supports the feasibility of developing replication-incompetent HAdVs as vaccines against pathogenic HAdVs.

HIV-1 infection has led to 1.329 million people living with the virus and 0.474 millions of deaths by the middle of 2024 in China. Achieving the goal of ending HIV/AIDS in China by 2030 has faced several grand challenges including currently less than 85% diagnostic rate, an estimated annual cost burden of 6.3 billion RMB for antiretroviral therapy (ART) alone, and the lack of therapeutic cure and preventive vaccine and so on. To address these challenges, Chinese scientists initiated the program of Grand Challenges on HIV/AIDS in China (GCC) in 2017. The inauguration symposium was held from November 30 to December 1, 2017 in Hong Kong—Asia’s World City—to commemorate the 10th anniversary of AIDS Institute at The University of Hong Kong and Comprehensive AIDS Research Center at Tsinghua University. The mission of the GCHAC is to advance HIV/AIDS prevention, prioritize research on therapeutic cure and vaccine, disseminate new scientific findings, and foster broader collaborations. Following the inaugural event, subsequent symposia were held at Fudan University in 2018, Sun Yat-Sen University in 2019, Tsinghua University in 2023, and Dali University in 2024. This review reports the scientific presentations and progresses made by the GCC scientists, highlighting efforts to combat HIV/AIDS in China.

Small cell lung cancer (SCLC) is an aggressively lethal malignancy with a high unmet medical need. Overexpression of Delta-like ligand 3 (DLL3) has been identified as a poor prognostic factor. Adoptive immunotherapy based on chimeric antigen receptor (CAR) T cells has been developed, however with significant adverse events. To address the critical need for an improved therapeutic intervention, we leveraged the ability of DLL3 targeted peripheral blood derived natural killer (PBNK) allogeneic cells therapy in treating SCLC. We describe preclinical in vitro and in vivo results demonstrating the antitumor efficacy of an off-the-shelf, cryopreserved DLL3 CAR-NK candidate. In addition, we make comprehensive comparison of PB units from different donors to establish criteria of starting materials selection for clinical and commercial supply of CAR-NK cells. PBNK cells were isolated from healthy donors with FcγRIIIA-158 (V/V, V/F) and propagated using feeder cells and cytokine cocktails. Various in vitro assays, including flow cytometry phenotyping, freeze-thaw viability/recovery, short-term and serial killing, cytokine releasing against tumor cells, were used for comprehensive function evaluation of PB units. DLL3 targeted CAR-NK cells were engineered by transducing donor-preselected NK cells with a retroviral vector encoding a DLL3 membrane-proximal epitope targeted scFv, a NK-optimized CAR backbone and a secreted IL15 armor. Activity of CAR-NK cells against target-expression SCLC cells was assessed in vitro and in vivo. PB Donors were selected with excellent NK expansion capacity and freeze/thaw recovery rate, stronger innate cytotoxicity and higher degranulation and intracellular IFN-γ buildup upon co-culturing with different tumor cells. The anti-DLL3 CAR was successfully transduced across all batches of CAR-NK cells derived from selected donors. NK-featured CAR backbone significantly enhanced expansion of NK cells and induced more activated NK phenotype compared to conventional CAR backbone. DLL3 CAR-NK cells was cytotoxic against DLL3+ tumor cells (SHP-77 and NCI-H2171 cells), and DLL3 CAR-NK cells combined with anti-PD-L1 antibodies could further enhance NK cells proliferation in response to tumor cells and could control multiple rounds of tumor cells re-challenge in vitro. Using a cell line derived xenograft mouse model, we showed that a single dose of cryopreserved DLL3 CAR-NK cells delayed tumor growth and prolonged mice survival. Synergistic in vivo antitumor efficacy and enhanced NK cell expansion in peripheral blood were observed when using CAR-NK combined with anti-PD-L1. Collectively, these results demonstrated the favorable manufacturability, potency, and safety of a DLL3 CAR-NK cells product and its potential as a novel allogeneic treatment option for patients with SCLC. Chao Wang, Tingting Liu, Qin Wang, Yanxue Gong, Ling Chen, Fanxiang Gao, Feng Zhou, Zhuoxiao Cao. A novel allogeneic anti-DLL3 CAR-NK cell therapy in treating small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6121.

Human respiratory syncytial virus (RSV) remains a leading cause of severe lower respiratory tract infections in infants and immunocompromised populations, causing approximately 160,000 annual deaths globally. Despite recent approvals of prefusion F (pre-F) protein-based vaccines (Arexvy, Abrysvo) for older adults and pregnant women, pediatric vaccine development faces unique challenges including enhanced respiratory disease (ERD) risks, maternal antibody interference, and immature infant immune responses. Meanwhile, G protein glycosylation variability and NS1/NS2-mediated interferon suppression remain the outstanding difficulties in structure-based vaccine design. Additionally, current animal models demonstrate notable constraints in virus replication, host susceptibility, immune responses, clinical symptoms, and ERD phenomena. This review synthesizes current obstacles and innovative strategies, highlighting that the selection of multi-antigen strategies, appropriate adjuvants, and the development of more precise preclinical animal models are critical elements that will determine the efficacy and safety of future RSV vaccines.

Live attenuated influenza vaccines (LAIVs) can elicit broad immunity, but rational attenuation strategies are limited. PR8 rp , a prototype influenza A virus with five segments extensively reprogrammed to use the least‐preferred synonymous codons is generated, introducing 1956 silent mutations and elevating CpG content. PR8 rp exhibits profound attenuation in vitro and ≈20 000‐fold lower virulence in mice, yet maintains vaccine‐level yields. A single intranasal dose confers sterilizing homologous protection and dose‐dependent cross‐protection against heterologous H1N1pdm and heterosubtypic H3N2 challenge, mediated by homologous neutralizing antibodies, cross‐reactive non‐neutralizing antibodies, and IFN‐γ–biased T cell responses. Mechanistic analyses reveal that attenuation resulted from defective NA genome packaging, loss of NS1 protein accumulation, augment of host antiviral responses, and heightened susceptibility to zinc‐finger antiviral protein–mediated restriction, rather than impaired RNA or protein synthesis. Applying this approach to a contemporary H1N1 strain yielded similar stable attenuation. These findings establish genome‐wide codon reprogramming as a versatile platform for safe, broadly protective LAIVs with multiple attenuation mechanisms.

ETHNOPHARMACOLOGICAL RELEVANCE:Suhuang antitussive capsule (SH) is the only clinically approved traditional Chinese patent medicine for the treatment of post-infectious cough (PIC). During the past decade, our lab has conducted intensive researches on SH, including its efficacy and mechanism on PIC, and determined that SH has favorable anti-inflammatory, antitussive, expectorant, and anti-asthmatic pharmacological effects. Recently, we found that vicenin-2 (VIC-2) could be detected in SH and showed activity in vitro primary screening on PIC. AIM OF THE STUDY:To investigate the therapeutic effects of VIC-2 on PIC and its potential mechanisms, and want to elucidate VIC-2 as one of the efficacious components of SH. MATERIALS AND METHODS:The PIC mouse model was established with lipopolysaccharide (LPS)-induced combined cigarette smoke (CS)-exposed ICR mice, while the in vitro assay was constructed to induce BEAS-2B cells with cigarette smoke extract (CSE). The therapeutic effects of VIC-2 on PIC in vitro and in vivo were assessed by pathological sections, cough assay, immune cell counting, and quantitative-polymerase chain reaction (Q-PCR). The mechanisms of VIC-2 on ferroptosis and mitophagy in PIC were further explored by cell viability assay, Prussian blue staining, lipid peroxidation assessment, confocal laser scanning microscopy, and western blotting. Subsequently, virtual docking, cellular thermal shift assay (CETSA), and drug affinity responsive target stability (DARTS) verified the target relationship between VIC-2 and LDL receptor-related protein 1 (LRP1). In addition, the link between LRP1 and mitophagy-dependent ferroptosis was explored by knocking down LRP1. RESULTS:VIC-2 significantly improved lung inflammation, oxidative stress, and airway remodeling in PIC and inhibited mitophagy-dependent ferroptosis, confirming that it is one of the antitussive components of SH for the treatment of PIC. LRP1 is one of the pharmacological targets of VIC-2, in which VIC-2 exerted the above effects through up-regulating LRP1 by influencing the LRP1-Parkin interaction. The blockade of LRP1 reversed the both in vitro and in vivo pharmacological activities of VIC-2. Furthermore, our results showed for the first time that defects in LRP1 lead to ferroptosis. CONCLUSION:This study demonstrates that VIC-2 inhibits mitophagy-dependent ferroptosis via LRP1 for the treatment of PIC, constituting one of the antitussive components of SH.

Human adenoviruses (Ad) are increasingly used as vaccine vectors, especially after Ad5, Ad26, and ChAdY25 (ChAdOx1) were employed as vectors for SARS-CoV-2 vaccines. So far, more than 116 adenovirus genotypes have been identified, divided into 7 species (A-G). Most adenoviruses do not cause diseases or are mildly pathogenic, with only species B and E leading to acute respiratory infections or conjunctival inflammation and species F causing gastrointestinal infections. Previous studies have shown that the seroprevalence of neutralizing antibodies against adenoviruses can be limiting when applying adenoviral vectors. On the other hand, for highly pathogenic adenoviruses, neutralizing antibodies is beneficial for preventing the diseases caused by these adenoviruses. Here, we summarized the studies on the seroprevalence of adenoviruses, especially adenoviruses that may be utilized as vectors for vaccine and gene therapy. We also analysed possible factors associated with the seroprevalence and neutralizing titres. Given the trend of increasing adenoviral vector application, it is necessary to continue the investigation of the seroprevalence of neutralizing antibodies against adenoviruses in different geographic locations and populations.

The persistence of latent viral reservoirs remains the major obstacle to eradicating human immunodeficiency virus (HIV). We herein found that ICP34.5 can act as an antagonistic factor for the reactivation of HIV latency by herpes simplex virus type I (HSV-1), and thus recombinant HSV-1 with ICP34.5 deletion could more effectively reactivate HIV latency than its wild-type counterpart. Mechanistically, HSV-ΔICP34.5 promoted the phosphorylation of HSF1 by decreasing the recruitment of protein phosphatase 1 (PP1α), thus effectively binding to the HIV LTR to reactivate the latent reservoirs. In addition, HSV-ΔICP34.5 enhanced the phosphorylation of IKKα/β through the degradation of IκBα, leading to p65 accumulation in the nucleus to elicit NF-κB pathway-dependent reactivation of HIV latency. Then, we constructed the recombinant HSV-ΔICP34.5 expressing simian immunodeficiency virus (SIV) env, gag, or the fusion antigen sPD1-SIVgag as a therapeutic vaccine, aiming to achieve a functional cure by simultaneously reactivating viral latency and eliciting antigen-specific immune responses. Results showed that these constructs effectively elicited SIV-specific immune responses, reactivated SIV latency, and delayed viral rebound after the interruption of antiretroviral therapy (ART) in chronically SIV-infected rhesus macaques. Collectively, these findings provide insights into the rational design of HSV-vectored therapeutic strategies for pursuing an HIV functional cure.

SARS-CoV-2 infection-induced hyper-inflammation links to the acute lung injury and COVID-19 severity. Identifying the primary mediators that initiate the uncontrolled hypercytokinemia is essential for treatments. Mast cells (MCs) are strategically located at the mucosa and beneficially or detrimentally regulate immune inflammations. In this study, we showed that SARS-CoV-2-triggered MC degranulation initiated alveolar epithelial inflammation and lung injury. SARS-CoV-2 challenge induced MC degranulation in ACE-2 humanized mice and rhesus macaques, and a rapid MC degranulation could be recapitulated with Spike-RBD binding to ACE2 in cells; MC degranulation altered various signaling pathways in alveolar epithelial cells, particularly, the induction of pro-inflammatory factors and consequential disruption of tight junctions. Importantly, the administration of clinical MC stabilizers for blocking degranulation dampened SARS-CoV-2-induced production of pro-inflammatory factors and prevented lung injury. These findings uncover a novel mechanism for SARS-CoV-2 initiating lung inflammation, and suggest an off-label use of MC stabilizer as immunomodulators for COVID-19 treatments.

Therapeutic vaccinations that enhance human immunodeficiency virus (HIV)-specific immunity hold promise for reducing reliance on antiretroviral therapy (ART). We previously developed an adenovirus vector-infected peripheral blood mononuclear cell (AVIP) as a prophylactic strategy that enhanced cellular immunity in macaques and significantly reduced set-point and peak simian immunodeficiency virus (SIV) loads following SIV challenge. However, its therapeutic efficacy remains to be fully explored. In this study, we improved AVIP by enhancing adenovirus entry into peripheral blood mononuclear cells (PBMCs) through in vitro co-incubation with granulocyte-macrophage colony-stimulating factor (GM-CSF). We constructed adenoviruses carrying SIV group-specific antigen (Gag), envelope (Env), and polymerase (Pol) and evaluated the therapeutic potential of autologous AVIP infusion in acute SIV-infected macaques. Compared with ART alone, AVIP in combination with ART elicited robust cellular immunity against SIV, effectively controlled SIV replication during ART, and delayed viral rebound and acquired immunodeficiency syndrome (AIDS) progression after ART discontinuation. Notably, 80% of macaques in AVIP+ART group maintain plasma virus control for at least 100 days after ART interruption. This sustained viral control is associated with vaccine-induced Pol-specific immune responses and reduced CD38 expression on CD8+ T cells. These findings support further investigation of AVIP as a therapeutic strategy against acute HIV infection.