CircRNA based multivalent neuraminidase vaccine induces broad protection against influenza viruses in mice.

Developing broad-spectrum influenza vaccines is crucial for influenza control and potential pandemic preparedness. Here, we reported a novel vaccine design utilizing circular RNA (circRNA) as a delivery platform for multi-subtype neuraminidases (NA) (influenza A N1, N2, and influenza B Victoria lineage NA) immunogens. Individual NA circRNA lipid nanoparticles (LNP) elicited robust NA-specific antibody responses with neuraminidase inhibition activity (NAI), preventing the virus from egressing and infecting neighboring cells. Additionally, the administration of circRNA LNP induced cellular immunity in mice. To achieve a universal influenza vaccine, we combined all three subtypes of NA circRNA-LNPs to generate a trivalent circRNA vaccine. The trivalent vaccine elicited a balanced antibody response against all three NA subtypes and a Th1-biased immune response in mice. Moreover, it protected mice against the lethal challenge of matched and mismatched H1N1, H3N2, and influenza B viruses, encompassing circulating and ancestral influenza virus strains. This study highlights the potential of delivering multiple NA antigens through circRNA-LNPs as a promising strategy for effectively developing a universal influenza vaccine against diverse influenza viruses.

A Recombinant Mosaic HAs Influenza Vaccine Elicits Broad-Spectrum Immune Response and Protection of Influenza a Viruses.

The annual co-circulation of two influenza A subtypes, H1N1 and H3N2, viruses in humans poses significant public health threats worldwide. However, the continuous antigenic drift and shift of influenza viruses limited the effectiveness of current seasonal influenza vaccines, necessitating the development of new vaccines against both seasonal and pandemic viruses. One potential solution to this challenge is to improve inactivated vaccines by including multiple T-cell epitopes. In this study, we designed stabilized trimeric recombinant mosaic HA proteins named HAm, which contain the most potential HA T-cell epitopes of seasonal influenza A virus. We further evaluated the antigenicity, hemagglutinin activity, and structural integrity of HAm and compared its immunogenicity and efficacy to a commercial quadrivalent inactivated influenza vaccine (QIV) in mice. Our results demonstrated that the HAm vaccine was able to induce broadly cross-reactive antibodies and T-cell responses against homologous, heterologous, and heterosubtypic influenza-naive mice. Additionally, the HAm antigens outperformed QIV vaccine antigens by eliciting protective antibodies against panels of antigenically drifted influenza vaccine strains from 2009 to 2024 and protecting against ancestral viruses' lethal challenge. These results suggest that the HAm vaccine is a promising potential candidate for future universal seasonal and pandemic influenza vaccine development.

Treatment as the Best Prevention: Twice-Yearly Lenacapavir, a Game Changer in Ending the AIDS Epidemic.

Despite over four decades of unremitting efforts since the discovery of acquired immunodeficiency syndrome (AIDS)/human immunodeficiency virus (HIV), there remains no cure for HIV nor a vaccine for its prevention [...].

ZIKV induces P62-mediated autophagic degradation of TRAF6 through TRAF6-NS1 interaction.

Tumor necrosis factor receptor-associated factor 6 (TRAF6) is crucial in flavivirus infections, modulating the host immune response through interactions with viral proteins. Despite its importance, the relationship between TRAF6 and Zika virus (ZIKV) remains poorly understood. Our prior proteomics analysis revealed reduced TRAF6 protein levels in ZIKV-infected human trophoblast cells compared to non-infected controls. Subsequent studies in cell models and murine tissues confirmed a significant reduction in both TRAF6 mRNA and protein levels post-ZIKV infection. Further investigations unveiled that ZIKV induces P62-mediated degradation of TRAF6, with NS1 identified as the primary contributor. Co-localization and interaction studies demonstrated that NS1 promotes the association of P62, a key autophagy mediator, with TRAF6. Notably, our findings revealed TRAF6 enhances ZIKV infection, NS1 ubiquitination, NS1 expression, and the production of inflammatory cytokines and chemokines. These insights highlight the intricate TRAF6-ZIKV relationship, offering potential for drug targeting NS1-TRAF6 interactions to manage ZIKV infections effectively.

Mosaic neuraminidase-based vaccine induces antigen-specific T cell responses against homologous and heterologous influenza viruses.

Seasonal influenza is an annually severe crisis for global public health, and an ideal influenza vaccine is expected to provide broad protection against constantly drifted strains. Compared to highly flexible hemagglutinin (HA), increasing data have demonstrated that neuraminidase (NA) might be a potential target against influenza variants. In the present study, a series of genetic algorithm-based mosaic NA were designed, and then cloned into recombinant DNA and replication-defective Vesicular Stomatitis Virus (VSV) vector as a novel influenza vaccine candidate. Our Results showed that DNA prime/VSV boost strategy elicited a robust NA-specific Th1-dominated immune response, but the traditional inactivated influenza vaccine elicited a Th2-dominated immune response. More importantly, the superior NA-specific immunity induced by our strategy could confer both a full protection against lethal homologous influenza challenge and a partial protection against heterologous influenza infection. These findings will provide insights on designing NA-based universal vaccine strategy against influenza variants.

A broad-spectrum multiepitope vaccine against seasonal influenza A and B viruses in mice.

BACKGROUND: Influenza viruses pose a persistent threat to global public health, necessitating the development of innovative and broadly effective vaccines. METHODS: This study focuses on a multiepitope vaccine (MEV) designed to provide broad-spectrum protection against different influenza viruses. The MEV, containing 19 B-cell linear epitopes, 7 CD4+ T cells, and 11 CD8+ T cells epitopes identified through enzyme-linked immunospot assay (ELISPOT) in influenza viruses infected mice, was administered through a regimen of two doses of DNA vaccine followed by one dose of a protein vaccine in C57BL/6 female mice. FINDINGS: Upon lethal challenge with both seasonal circulating strains (H1N1, H3N2, BV, and BY) and historical strains (H1N1-PR8 and H3N2-X31), MEV demonstrated substantial protection against different influenza seasonal strains, with partial efficacy against historical strains. Notably, the increased germinal centre B cells and antibody-secreting cells, along with robust T cell immune responses, highlighted the comprehensive immune defence elicited by MEV. Elevated hemagglutinin inhibition antibody was also observed against seasonal circulating and historical strains. Additionally, mice vaccinated with MEV exhibited significantly lower counts of inflammatory cells in the lungs compared to negative control groups. INTERPRETATION: Our results demonstrated the efficacy of a broad-spectrum MEV against influenza viruses in mice. Conducting long-term studies to evaluate the durability of MEV-induced immune responses and explore its potential application in diverse populations will offer valuable insights for the continued advancement of this promising vaccine. FUNDING: Funding bodies are described in the Acknowledgments section.

c-FLIP facilitates ZIKV infection by mediating caspase-8/3-dependent apoptosis.

c-FLIP functions as a dual regulator of apoptosis and inflammation, yet its implications in Zika virus (ZIKV) infection remain partially understood, especially in the context of ZIKV-induced congenital Zika syndrome (CZS) where both apoptosis and inflammation play pivotal roles. Our findings demonstrate that c-FLIP promotes ZIKV infection in placental cells and myeloid-derived macrophages, involving inflammation and caspase-8/3-mediated apoptosis. Moreover, our observations reveal that c-FLIP augments ZIKV infection in multiple tissues, including blood cell, spleen, uterus, testis, and the brain of mice. Notably, the partial deficiency of c-FLIP provides protection to embryos against ZIKV-induced CZS, accompanied by a reduction in caspase-3-mediated apoptosis. Additionally, we have found a distinctive parental effect of c-FLIP influencing ZIKV replication in fetal heads. In summary, our study reveals the critical role of c-FLIP as a positive regulator in caspase-8/3-mediated apoptosis during ZIKV infection, significantly contributing to the development of CZS.

Network-based approach for drug repurposing against mpox.

The current outbreak of mpox presents a significant threat to the global community. However, the lack of mpox-specific drugs necessitates the identification of additional candidates for clinical trials. In this study, a network medicine framework was used to investigate poxviruses-human interactions to identify potential drugs effective against the mpox virus (MPXV). The results indicated that poxviruses preferentially target hubs on the human interactome, and that these virally-targeted proteins (VTPs) tend to aggregate together within specific modules. Comorbidity analysis revealed that mpox is closely related to immune system diseases. Based on predicted drug-target interactions, 268 drugs were identified using the network proximity approach, among which 23 drugs displaying the least side-effects and significant proximity to MPXV were selected as the final candidates. Lastly, specific drugs were explored based on VTPs, differentially expressed proteins, and intermediate nodes, corresponding to different categories. These findings provide novel insights that can contribute to a deeper understanding of the pathogenesis of MPXV and development of ready-to-use treatment strategies based on drug repurposing.

Influence of grandchildren on COVID-19 vaccination uptake among older adults in China: a parallel-group, cluster-randomized controlled trial.

The uptake of COVID-19 booster vaccination among older adults in China is suboptimal. Here, we report the results of a parallel-group cluster-randomized controlled trial evaluating the efficacy of promoting COVID-19 booster vaccination among grandparents (≥60 years) through a health education intervention delivered to their grandchildren (aged ≥16 years) in a Chinese cohort (Chinese Clinical Trial Registry: ChiCTR2200063240 ). The primary outcome was the uptake rate of COVID-19 booster dose among grandparents. Secondary outcomes include grandparents' attitude and intention to get a COVID-19 booster dose. A total of 202 college students were randomized 1:1 to either the intervention arm of web-based health education and 14 daily reminders (n = 188 grandparents) or control arm (n = 187 grandparents) and reported their grandparents' COVID-19 booster vaccination status at baseline and 21 days. Grandparents in the intervention arm were more likely to receive COVID-19 booster vaccination compared to control cohort (intervention, 30.6%; control, 16.9%; risk ratio = 2.00 (95% CI, 1.09 to 3.66)). Grandparents in the intervention arm also had greater attitude change (ß = 0.28 (95% CI, 0.04 to 0.52)) and intention change (ß = 0.32 (95% CI, 0.12 to 0.52)) to receive a COVID-19 booster dose. Our results show that an educational intervention targeting college students increased COVID-19 booster vaccination uptake among grandparents in China.

Association between Statins Administration and Influenza Susceptibility: A Systematic Review and Meta-Analysis of Longitudinal Studies.

Previous studies reported that the association between statins use and influenza infection was contradictory. A systematic review and meta-analysis of longitudinal studies were performed to determine the association between statins use and influenza susceptibility. The literature search was conducted in PubMed, Embase, and Web of Science, from each database's inception to 21 May 2023. The fixed effect model and random effects model were used for data synthesis. In our study, a total of 1,472,239 statins users and 1,486,881 statins non-users from five articles were included. The pooled risk ratio (RR) of all included participants was 1.05 (95% CI: 1.03-1.07), and there were still significant differences after adjusting for vaccination status. Of note, RR values in statins users were 1.06 (95% CI: 1.03-1.08) in people aged ≥60 years old and 1.05 (95% CI: 1.03-1.07) in participant groups with a higher proportion of females. Administration of statins might be associated with an increased risk of influenza infection, especially among females and elderly people. For those people using statins, we should pay more attention to surveillance of their health conditions and take measures to prevent influenza infection.

The 2nd China Vaccinology Integrated Innovation & Teaching Development Conference: Promoting the construction of vaccinology discipline system.

The 2nd China Vaccinology Integrated Innovation & Teaching Development Conference was held in Sun Yat-sen University, Shenzhen, 18-19, November 2023. Over 200 participants in the field of Vaccinology gathered together to address challenges and issues relevant to vaccine education and training courses, research, and public health programs in China. The conference themed "Promoting the Integrated and Innovative Development of Vaccinology through Collective Efforts." The conference was organized by the China Association of Vaccine (CAV) and hosted by Vaccinology Education Professional Committee of CAV, and School of Public Health (Shenzhen), Sun Yat-sen University. Other partners included the Medical Virology Branch of the Chinese Medical Association, the editorial committee of the Chinese Journal of Preventive Medicine, Human Vaccines & Immunotherapeutics, and the People's Medical Publishing House. The 1st conference was held in Hangzhou, in October 2020.

In silico design of a broad-spectrum multiepitope vaccine against influenza virus.

Influenza remains a global health concern due to its potential to cause pandemics as a result of rapidly mutating influenza virus strains. Existing vaccines often struggle to keep up with these rapidly mutating flu viruses. Therefore, the development of a broad-spectrum peptide vaccine that can stimulate an optimal antibody response has emerged as an innovative approach to addressing the influenza threat. In this study, an immunoinformatic approach was employed to rapidly predict immunodominant epitopes from different antigens, aiming to develop an effective multiepitope influenza vaccine (MEV). The immunodominant B-cell linear epitopes of seasonal influenza strains hemagglutinin (HA) and neuraminidase (NA) were predicted using an antibody-peptide microarray, involving a human cohort including vaccinees and infected patients. On the other hand, bioinformatics tools were used to predict immunodominant cytotoxic T-cell (CTL) and helper T-cell (HTL) epitopes. Subsequently, these epitopes were evaluated by various immunoinformatic tools. Epitopes with high antigenicity, high immunogenicity, non-allergenicity, non-toxicity, as well as exemplary conservation were then connected in series with appropriate linkers and adjuvants to construct a broad-spectrum MEV. Moreover, the structural analysis revealed that the MEV candidates exhibited good stability, and the docking results demonstrated their strong affinity to Toll-like receptors 4 (TLR4). In addition, molecular dynamics simulation confirmed the stable interaction between TLR4 and MEVs. Three injections with MEVs showed a high level of B-cell and T-cell immune responses according to the immunological simulations in silico. Furthermore, in-silico cloning was performed, and the results indicated that the MEVs could be produced in considerable quantities in Escherichia coli (E. coli). Based on these findings, it is reasonable to create a broad-spectrum MEV against different subtypes of influenza A and B viruses in silico.

Rapid Induction of Long-Lasting Systemic and Mucosal Immunity via Thermostable Microneedle-Mediated Chitosan Oligosaccharide-Encapsulated DNA Nanoparticles.

Most existing vaccines, delivered by intramuscular injection (IM), are typically associated with stringent storage requirements under cold-chain distribution and professional administration by medical personnel and often result in the induction of weak mucosal immunity. In this context, we reported a microneedle (MN) patch to deliver chitosan oligosaccharide (COS)-encapsulated DNA vaccines (DNA@COS) encoding spike and nucleocapsid proteins of SARS-CoV-2 as a vaccination technology. Compared with IM immunization, intradermal administration via the MN-mediated DNA vaccine effectively induces a comparable level of neutralizing antibody against SARS-CoV-2 variants. Surprisingly, we found that MN-mediated intradermal immunization elicited superior systemic and mucosal T cell immunity with enhanced magnitude, polyfunctionality, and persistence. Importantly, the DNA@COS nanoparticle vaccine loaded in an MN patch can be stored at room temperature for at least 1 month without a significant decrease of its immunogenicity. Mechanically, our strategy enhanced dendritic cell maturation and antiviral immunity by activating the cGAS-STING-mediated IFN signaling pathway. In conclusion, this work provides valuable insights for the rapid development of an easy-to-administer and thermostable technology for mucosal vaccines.

IronForge: An Open, Secure, Fair, Decentralized Federated Learning.

Federated learning (FL) offers an effective learning architecture to protect data privacy in a distributed manner. However, the inevitable network asynchrony, overdependence on a central coordinator, and lack of an open and fair incentive mechanism collectively hinder FL's further development. We propose IronForge, a new generation of FL framework, that features a directed acyclic graph (DAG)-based structure, where nodes represent uploaded models, and referencing relationships between models form the DAG that guides the aggregation process. This design eliminates the need for central coordinators to achieve fully decentralized operations. IronForge runs in a public and open network and launches a fair incentive mechanism by enabling state consistency in the DAG. Hence, the system fits in networks where training resources are unevenly distributed. In addition, dedicated defense strategies against prevalent FL attacks on incentive fairness and data privacy are presented to ensure the security of IronForge. Experimental results based on a newly developed test bed FLSim highlight the superiority of IronForge to the existing prevalent FL frameworks under various specifications in performance, fairness, and security. To the best of our knowledge, IronForge is the first secure and fully decentralized FL (DFL) framework that can be applied in open networks with realistic network and training settings.

Special Issue: "Innate Immunity to Virus Infection, 1st Edition".

Frequent outbreaks of emerging and re-emerging pathogenic viruses have become one of the major challenges for global public health [...].

Perception and willingness toward various immunization routes for COVID-19 vaccines: a cross-sectional survey in China.

Background: To date, most vaccines, including the COVID-19 vaccine, are mainly administered by intramuscular injection, which might lead to vaccine hesitancy in some populations due to needle fear. Alternatively, needle-free immunization technology is extensively developed to improve the efficacy and acceptance of vaccination. However, there is no study to report the perception and willingness toward various immunization routes of the COVID-19 vaccine in the general population. Methods: A cross-sectional survey was conducted nationwide using an online questionnaire. Bivariate analyses were undertaken to assess variable associations among the participants who reported a hesitancy to receive the COVID-19 booster vaccination. Multivariable logistic regression with a backward step-wise approach was used to analyze the predicted factors associated with the willingness to receive the COVID-19 booster vaccination. Results: A total of 3,244 valid respondents were included in this survey, and 63.2% of participants thought they had a good understanding of intramuscular injection, but only 20.7, 9.2, 9.4, and 6.0% of participants had a self-perceived good understanding of inhalation vaccine, nasal spray vaccine, oral vaccine, and microneedle patch vaccine. Correspondingly, there was high acceptance for intramuscular injection (76.5%), followed by oral inhalation (64.4%) and nasal spray (43.0%). Those participants who were only willing to receive an intramuscular vaccine had less vaccine knowledge (OR = 0.78; 95% CI: 0.65-0.94) than those who were willing to receive a needle-free vaccine (OR = 1.97; 95% CI: 1.52-2.57). Some factors were found to be associated with vaccine hesitancy toward booster COVID-19 vaccination. Conclusion: Needle-free vaccination is a promising technology for the next generation of vaccines, but we found that intramuscular injection was still the most acceptable immunization route in this survey. One major reason might be that most people lack knowledge about needle-free vaccination. We should strengthen the publicity of needle-free vaccination technology, and thus improve the acceptance and coverage of vaccination in different populations.

A mosaic influenza virus-like particles vaccine provides broad humoral and cellular immune responses against influenza A viruses.

The development of a universal influenza vaccine to elicit broad immune responses is essential in reducing disease burden and pandemic impact. In this study, the mosaic vaccine design strategy and genetic algorithms were utilized to optimize the seasonal influenza A virus (H1N1, H3N2) hemagglutinin (HA) and neuraminidase (NA) antigens, which also contain most potential T-cell epitopes. These mosaic immunogens were then expressed as virus-like particles (VLPs) using the baculovirus expression system. The immunogenicity and protection effectiveness of the mosaic VLPs were compared to the commercial quadrivalent inactivated influenza vaccine (QIV) in the mice model. Strong cross-reactive antibody responses were observed in mice following two doses of vaccination with the mosaic VLPs, with HI titers higher than 40 in 15 of 16 tested strains as opposed to limited cross HI antibody levels with QIV vaccination. After a single vaccination, mice also show a stronger level of cross-reactive antibody responses than the QIV. The QIV vaccinations only elicited NI antibodies to a small number of vaccine strains, and not even strong NI antibodies to its corresponding vaccine components. In contrast, the mosaic VLPs caused robust NI antibodies to all tested seasonal influenza virus vaccine strains. Here, we demonstrated the mosaic vaccines induces stronger cross-reactive antibodies and robust more T-cell responses compared to the QIV. The mosaic VLPs also provided protection against challenges with ancestral influenza A viruses of both H1 and H3 subtypes. These findings indicated that the mosaic VLPs were a promising strategy for developing a broad influenza vaccine in future.

Effect of seasonal coronavirus immune imprinting on the immunogenicity of inactivated COVID-19 vaccination.

Background: Pre-existing cross-reactive immunity among different coronaviruses, also termed immune imprinting, may have a comprehensive impact on subsequent SARS-CoV-2 infection and COVID-19 vaccination effectiveness. Here, we aim to explore the interplay between pre-existing seasonal coronaviruses (sCoVs) antibodies and the humoral immunity induced by COVID-19 vaccination. Methods: We first collected serum samples from healthy donors prior to COVID-19 pandemic and individuals who had received COVID-19 vaccination post-pandemic in China, and the levels of IgG antibodies against sCoVs and SARS-CoV-2 were detected by ELISA. Wilcoxon rank sum test and chi-square test were used to compare the difference in magnitude and seropositivity rate between two groups. Then, we recruited a longitudinal cohort to collect serum samples before and after COVID-19 vaccination. The levels of IgG antibodies against SARS-CoV-2 S, S1, S2 and N antigen were monitored. Association between pre-existing sCoVs antibody and COVID-19 vaccination-induced antibodies were analyzed by Spearman rank correlation. Results: 96.0% samples (339/353) showed the presence of IgG antibodies against at least one subtype of sCoVs. 229E and OC43 exhibited the highest seroprevalence rates at 78.5% and 72.0%, respectively, followed by NL63 (60.9%) and HKU1 (52.4%). The levels of IgG antibodies against two ß coronaviruses (OC43 and HKU1) were significantly higher in these donors who had inoculated with COVID-19 vaccines compared to pre-pandemic healthy donors. However, we found that COVID-19 vaccine-induced antibody levels were not significant different between two groups with high levelor low level of pre-existing sCoVs antibody among the longitudinal cohort. Conclusion: We found a high prevalence of antibodies against sCoVs in Chinese population. The immune imprinting by sCoVs could be reactivated by COVID-19 vaccination, but it did not appear to be a major factor affecting the immunogenicity of COVID-19 vaccine. These findings will provide insights into understanding the impact of immune imprinting on subsequent multiple shots of COVID-19 vaccines.

High Genetic Diversity of HIV-1 and Active Transmission Clusters among Male-to-Male Sexual Contacts (MMSCs) in Zhuhai, China.

Monitoring genetic diversity and recent HIV infections (RHIs) is critical for understanding HIV epidemiology. Here, we report HIV-1 genetic diversity and RHIs in blood samples from 190 HIV-positive MMSCs in Zhuhai, China. MMSCs with newly reported HIV were enrolled from January 2020 to June 2022. A nested PCR was performed to amplify the HIV polymerase gene fragments at HXB2 positions 2604-3606. We constructed genetic transmission network at both 0.5% and 1.5% distance thresholds using the Tamura-Nei93 model. RHIs were identified using a recent infection testing algorithm (RITA) combining limiting antigen avidity enzyme immunoassay (LAg-EIA) assay with clinical data. The results revealed that 19.5% (37/190) were RHIs and 48.4% (92/190) were CRF07_BC. Two clusters were identified at a 0.5% distance threshold. Among them, one was infected with CRF07_BC for the long term, and the other was infected with CRF55_01B recently. We identified a total of 15 clusters at a 1.5% distance threshold. Among them, nine were infected with CRF07_BC subtype, and RHIs were found in 38.8% (19/49) distributed in eight genetic clusters. We identified a large active transmission cluster (n = 10) infected with a genetic variant, CRF79_0107. The multivariable logistic regression model showed that clusters were more likely to be RHIs (adjusted OR: 3.64, 95% CI: 1.51~9.01). The RHI algorithm can help to identify recent or ongoing transmission clusters where the prevention tools are mostly needed. Prompt public health measures are needed to contain the further spread of active transmission clusters.

Arsenic trioxide-induced apoptosis contributes to suppression of viral reservoir in SIV-infected rhesus macaques.

Latent viral reservoir is recognized as the major obstacle to achieving a functional cure for HIV infection. We previously reported that arsenic trioxide (As2O3) combined with antiretroviral therapy (ART) can reactivate the viral reservoir and delay viral rebound after ART interruption in chronically simian immunodeficiency virus (SIV)-infected macaques. In this study, we further investigated the effect of As2O3 independent of ART in chronically SIV-infected macaques. We found that As2O3-only treatment significantly increased the CD4/CD8 ratio, improved SIV-specific T cell responses, and reactivated viral latency in chronically SIVmac239-infected macaques. RNA-sequencing analysis revealed that As2O3 treatment downregulated the expression levels of genes related to HIV entry and infection, while the expression levels of genes related to transcription initiation, cell apoptosis, and host restriction factors were significantly upregulated. Importantly, we found that As2O3 treatment specifically induced apoptosis of SIV-infected CD4+ T cells. These findings revealed that As2O3 might not only impact viral latency, but also induce the apoptosis of HIV-infected cells and thus block the secondary infection of bystanders. Moreover, we investigated the therapeutic potential of this regimen in acutely SIVmac239-infected macaques and found that As2O3 + ART treatment effectively restored the CD4+ T cell count, delayed disease progression, and improved survival in acutely SIV-infected macaques. In sum, this work provides new insights to develop As2O3 as a component of the "shock-and-kill" strategy toward HIV functional cure. IMPORTANCE Although antiretroviral therapy (ART) can effectively suppress the viral load of AIDS patients, it cannot functionally cure HIV infection due to the existence of HIV reservoir. Strategies toward HIV functional cure are still highly anticipated to ultimately end the pandemic of AIDS. Herein, we investigated the direct role of As2O3 independent of ART in chronically SIV-infected macaques and explored the underlying mechanisms of the potential of As2O3 in the treatment of HIV/SIV infection. Meanwhile, we investigated the therapeutic effects of ART+As2O3 in acutely SIVmac239-infected macaques. This study showed that As2O3 has the potential to be launched into the "shock-and-kill" strategy to suppress HIV/SIV reservoir due to its latency-reversing and apoptosis-inducing properties.