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Dihalogenated nitrophenols (2,6-DHNPs), an emerging group of aromatic disinfection byproducts (DBPs) detected in drinking water, have limited available information regarding their persistence and toxicological risks. The present study found that 2,6-DHNPs are resistant to major drinking water treatment processes (sedimentation and filtration) and households methods (boiling, filtration, microwave irradiation, and ultrasonic cleaning). To further assess their health risks, we conducted a series of toxicology studies using zebrafish embryos as the model organism. Our findings reveal that these emerging 2,6-DHNPs showed lethal toxicity 248 times greater than that of the regulated DBP, dichloroacetic acid. Specifically, at sublethal concentrations, exposure to 2,6-DHNPs generated reactive oxygen species (ROS), caused apoptosis, inhibited cardiac looping, and induced cardiac failure in zebrafish. Remarkably, the use of a ROS scavenger, N-acetyl-l-cysteine, considerably mitigated these adverse effects, emphasizing the essential role of ROS in 2,6-DHNP-induced cardiotoxicity. Our findings highlight the cardiotoxic potential of 2,6-DHNPs in drinking water even at low concentrations of 19 μg/L and the beneficial effect of N-acetyl-l-cysteine in alleviating the 2,6-DHNP-induced cardiotoxicity. This study underscores the urgent need for increased scrutiny of these emerging compounds in public health discussions.

ABSTRACT 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.

3C proteases (3Cpros) of picornaviruses and 3C-like proteases (3CLpros) of coronaviruses and caliciviruses represent a group of structurally and functionally related viral proteases that play pleiotropic roles in supporting the viral life cycle and subverting host antiviral responses. The design and screening for 3C/3CLpro inhibitors may contribute to the development broad-spectrum antiviral therapeutics against viral diseases related to these three families. However, current screening strategies cannot simultaneously assess a compound’s cytotoxicity and its impact on enzymatic activity and protease-mediated physiological processes. The viral induction of stress granules (SGs) in host cells acts as an important antiviral stress response by blocking viral translation and stimulating the host immune response. Most of these viruses have evolved 3C/3CLpro-mediated cleavage of SG core protein G3BP1 to counteract SG formation and disrupt the host defense. Yet, there are no SG-based strategies screening for 3C/3CLpro inhibitors. Here, we developed a fluorescence resonance energy transfer (FRET) and SG dual-based system to screen for 3C/3CLpro inhibitors in living cells. We took advantage of FRET to evaluate the protease activity of poliovirus (PV) 3Cpro and live-monitor cellular SG dynamics to cross-verify its effect on the host antiviral response. Our drug screen uncovered a novel role of Telaprevir and Trifluridine as inhibitors of PV 3Cpro. Moreover, Telaprevir and Trifluridine also modulated 3Cpro-mediated physiological processes, including the cleavage of host proteins, inhibition of the innate immune response, and consequent facilitation of viral replication. Taken together, the FRET and SG dual-based system exhibits a promising potential in the screening for inhibitors of viral proteases that cleave G3BP1.

Abstract The latent viral reservoir is the source of viral rebound after interruption of antiretroviral therapy (ART) and is the major obstacle in eradicating the latent human immunodeficiency virus‐1 (HIV‐1). In this study, arsenic class of mineral, arsenic trioxide, clinically approved for treating acute promyelocytic leukemia, is demonstrated to reactivate latent provirus in CD4+ T cells from HIV‐1 patients and Simian immunodeficiency virus (SIV)‐infected macaques, without significant systemic T cell activation and inflammatory responses. In a proof‐of‐concept study using chronically SIVmac239‐infected macaques, arsenic trioxide combined with ART delays viral rebound after ART termination, reduces the integrated SIV DNA copies in CD4+ T cells, and restores CD4+ T cells counts in vivo. Most importantly, half of arsenic trioxide‐treated macaques show no detectable viral rebound in the plasma for at least 80 days after ART discontinuation. Mechanistically, the study reveals that CD4 receptors and CCR5 co‐receptors of CD4+ T cells are significantly downregulated by arsenic trioxide treatment, which reduces susceptibility to infection after provirus reactivation. Furthermore, an increase in SIV‐specific immune responses after arsenic trioxide treatment may contribute to suppression of viral rebound. This work suggests that arsenic trioxide in combination with ART is a novel regimen in down‐sizing or even eradicating latent HIV‐1 reservoir.

Though immune correlates for protection are still under investigation, potent cytotoxic T lymphocyte responses are desirable for an ideal HIV-1 vaccine. PD-1 blockade enhances SIV-specific CD8+ T cells. However, little information has been reported about how it affects the immunogenicity and protection of prophylactic SIV vaccines in nonhuman primates. Here, we show that PD-1 blockade during vaccination substantially improved protective efficacy in SIV challenged macaques. The PD-1 pathway was blocked using a monoclonal antibody specific to human PD-1. Administration of this antibody effectively augmented and sustained vaccine-induced SIV-specific T cell responses for more than 42 weeks after first immunization in rhesus monkeys, as compared with SIV vaccination only. Importantly, after intrarectally repeated low-dosage challenge with highly pathogenic SIVmac239, monkeys with PD-1 blockade during vaccination achieved full protection against incremental viral doses of up to 50,000 TICD50. These findings highlight the importance of PD-1 blockade during vaccination for the development of HIV vaccines.

Background: This study aims to improve the understanding of lymphoma-associated hemophagocytic syndrome, and find effective methods to identify and manage this fatal disease. Methods: Patients diagnosed with non-Hodgkin lymphoma-associated hemophagocytic syndrome from January 2008 to December 2022 in our center were included. Univariate and multivariate analyses were also conducted using the Cox proportional hazards model. Results: Among 26 patients, 22 patients were diagnosed with T/NK cell lymphoma, while 4 patients were diagnosed with diffuse large B cell lymphoma. A total of 16 patients died with a median follow-up of 71 (26, 236) days. Compared with B cell lymphoma-associated hemophagocytic syndrome patients, T/NK cell lymphoma patients are younger, have lower platelet count, fibrinogen concentration, and serum albumin, have higher blood ß2-microglobulin levels and ferritin, are more likely to be infected with Epstein-Barr virus, are more inclined have a simultaneously occurrence of lymphoma and hemophagocytic syndrome. In multivariate analysis, fibrinogen, albumin, cholinesterase, uric acid, triglyceride, and ferritin are significantly associated with overall mortality. Conclusions: LAHS is a rare disease with poor prognosis. Early anti-inflammatory treatment combined with antilymphoma therapy can improve the overall survival time of patients. Prospective multi-center studies with larger sample sizes and longer follow-up periods are needed to further investigate optimal treatment and prognosis. [ABSTRACT FROM AUTHOR]

Background: Only a few epidemiological studies have illuminated the association between pesticide exposure and female infertility. However, evidence of the available data is restricted and also controversial. Vitamin D supplement was considered as having a beneficial effect on fertility. So, the purpose of our study is to assess the effect of dietary vitamin D consumption on the relationship between pesticide exposure in home and female infertility. Methods: There were a total of 2,968 subjects from the National Health and Nutrition Examination Survey (NHANES), 2011 - 2018. The daily vitamin D intake was divided into two groups high intake (= 6 µg/d) and low intake (< 6 µg/d). Multi-variable logistic regression analysis was used to assess the relationship among vitamin D intake, pesticide exposure, and female infertility. Results: We found a significant association between household pesticide exposure and infertility on a basis of a fully-adjusted model (OR 1.61; 95% CI 1.1 - 2.37). Furthermore, the relationship between pesticide exposure and infertility differed from low vitamin D intake group (OR 3.96; 95% CI 1.77 - 8.86) and high intake group (OR 1.36, 95% CI: 0.86 - 2.16), and p for interaction is 0.043 stratified by vitamin D intake. Conclusions: A significant association of female infertility with pesticide exposure in home is modified by dietary vitamin D consumption. This was the first study to demonstrate that dietary vitamin D may alter associations of human female infertility with pesticide exposure in home. [ABSTRACT FROM AUTHOR]

The persistence of cells latently infected with HIV-1, named the latent reservoir, is the major barrier to HIV-1 eradication, and the formation and maintenance of the latent reservoir might be exacerbated by activation of the immunoinhibitory pathway and dysfunction of CD81 T cells during HIV-1 infection. Our previous findings demonstrated that prophylactic vaccination combined with PD-1 blockade generated distinct immune response profiles and conferred effective control of highly pathogenic SIVmac239 infection in rhesus macaques. However, to our surprise, herein we found that a therapeutic vaccination in combination with PD-1 blockade resulted in activation of the viral reservoir, faster viral rebound after treatment interruption, accelerated AIDS progression, and, ultimately, death in chronically SIVinfected macaques after antiretroviral therapy (ART) interruption. Our study further demonstrated that the SIV provirus was preferentially enriched in PD-11CD41 T cells due to their susceptibility to viral entry, potent proliferative ability, and inability to perform viral transcription. In addition, the viral latency was effectively reactivated upon PD-1 blockade. Together, these results suggest that PD-1 blockade may be a double-edged sword for HIV-1 immunotherapy and provide important insight toward the rational design of immunotherapy strategies for an HIV-1 cure. [ABSTRACT FROM AUTHOR]