Current drugs for HIV-1: from challenges to potential in HIV/AIDS.

The human immunodeficiency virus (HIV) persists in latently infected CD4+T cells and integrates with the host genome until cell death. Acquired immunodeficiency syndrome (AIDS) is associated with HIV-1. Possibly, treating HIV/AIDS is an essential but challenging clinical goal. This review provides a detailed account of the types and mechanisms of monotherapy and combination therapy against HIV-1 and describes nanoparticle and hydrogel delivery systems. In particular, the recently developed capsid inhibitor (Lenacapavir) and the Ainuovirine/tenofovir disoproxil fumarate/lamivudine combination (ACC008) are described. It is interestingly to note that the lack of the multipass transmembrane proteins serine incorporator 3 (SERINC3) and the multipass transmembrane proteins serine incorporator 5 (SERINC5) may be one of the reasons for the enhanced infectivity of HIV-1. This discovery of SERINC3 and SERINC5 provides new ideas for HIV-1 medication development. Therefore, we believe that in treating AIDS, antiviral medications should be rationally selected for pre-exposure and post-exposure prophylaxis to avoid the emergence of drug resistance. Attention should be paid to the research and development of new drugs to predict HIV mutations as accurately as possible and to develop immune antibodies to provide multiple guarantees for the cure of AIDS.

Cytomembrane Trafficking Pathways of Connexin 26, 30, and 43.

The connexin gene family is the most prevalent gene that contributes to hearing loss. Connexins 26 and 30, encoded by GJB2 and GJB6, respectively, are the most abundantly expressed connexins in the inner ear. Connexin 43, which is encoded by GJA1, appears to be widely expressed in various organs, including the heart, skin, the brain, and the inner ear. The mutations that arise in GJB2, GJB6, and GJA1 can all result in comprehensive or non-comprehensive genetic deafness in newborns. As it is predicted that connexins include at least 20 isoforms in humans, the biosynthesis, structural composition, and degradation of connexins must be precisely regulated so that the gap junctions can properly operate. Certain mutations result in connexins possessing a faulty subcellular localization, failing to transport to the cell membrane and preventing gap junction formation, ultimately leading to connexin dysfunction and hearing loss. In this review, we provide a discussion of the transport models for connexin 43, connexins 30 and 26, mutations affecting trafficking pathways of these connexins, the existing controversies in the trafficking pathways of connexins, and the molecules involved in connexin trafficking and their functions. This review can contribute to a new way of understanding the etiological principles of connexin mutations and finding therapeutic strategies for hereditary deafness.

11.4 T ultra-high static magnetic field has no effect on morphology but induces upregulation of TNF signaling pathway based on transcriptome analysis in zebrafish embryos.

As magnetic resonance imaging (MRI) scanners with ultra-high field (UHF) have optimal performance, scientists have been working to develop high-performance devices with strong magnetic fields to improve their diagnostic potential. However, whether an MRI scanner with UHF poses a risk to the safety of the organism require further evaluation. This study evaluated the effects of 11.4 Tesla (T) UHF on embryonic development using a zebrafish model. Multiple approaches, including morphological parameters, physiological behaviors, and analyses of the transcriptome at the molecular level, were determined during 5 days after laboratory-controlled exposure from 6 hour post fertilization (hpf) to 24 hpf. No significant effects were observed in embryo mortality, hatching rate, body length, Left-Right patterning, locomotor behavior, etc. RNA-sequencing analysis revealed up-regulated tumor necrosis factor (TNF) inflammatory factors and activated TNF signaling pathways in the 11.4 T exposure group. The results were further validated using qPCR. Our findings indicate that although UHF exposure under 11.4 T has no effect on the development of zebrafish embryos, it has specific effects on the immune response that require further investigation.

Coxsackievirus A6 Infection Causes Neurogenic Pathogenesis in a Neonatal Murine Model.

Coxsackievirus A6 (CVA6), a member of species A enterovirus, is associated with outbreaks of hand-foot-and-mouth disease and causes a large nationwide burden of disease. However, the molecular pathogenesis of CVA6 remains unclear. In the present study, we established a suckling Institute of Cancer Research (ICR) mouse infection model to explore the neural pathogenicity of CVA6. Five-day-old mice infected with CVA6 strain F219 showed lethargy and paralysis, and died 5 or 6 days after infection via IM injection. Cerebral edema and neuronal cell swelling were observed in the infected brain tissue, and we found that the CVA6 VP1 antigen could co-localize with GFAP-positive astrocytes in infected mouse brain using an immunofluorescence assay. CVA6 strain F219 can also infect human glioma (U251) cells. Transcriptome analysis of brain tissues from infected mice and infected U251 cells showed that significantly differentially expressed genes were enriched in antiviral and immune response and neurological system processes. These results indicate that CVA6 could cause neural pathogenesis and provide basic data for exploring the mechanism of how host-cell interactions affect viral replication and pathogenesis. Importance: Coxsackievirus A6 (CVA6) surpasses the two main pathogens, enterovirus 71 (EV-A71) and coxsackievirus A16 (CVA16), which are the leading pathogens causing HFMD in many provinces of China. In our study, CVA6 infection caused neurogenic pathogenesis in a neonatal murine model, manifesting as cerebral edema and neuronal cell swelling, CVA6 VP1 antigen could co-localize with GFAP-positive astrocytes in the infected mouse brain. Based on CVA6-infected brain tissue and U251 cell transcriptome analysis, we found upregulated antiviral and immune response-related genes such as Zbp1, Usp18, Oas2, Irf7, Ddx60, Ifit3, Ddx58, and Isg15, while the neurological system process-related genes were downregulated, including Fcrls, Ebnrb, Cdk1, and Anxa5.

Cellular Processes Induced by HSV-1 Infections in Vestibular Neuritis.

Herpesvirus is a prevalent pathogen that primarily infects human epithelial cells and has the ability to reside in neurons. In the field of otolaryngology, herpesvirus infection primarily leads to hearing loss and vestibular neuritis and is considered the primary hypothesis regarding the pathogenesis of vestibular neuritis. In this review, we provide a summary of the effects of the herpes virus on cellular processes in both host cells and immune cells, with a focus on HSV-1 as illustrative examples.

Induction of cardiotoxicity in zebrafish embryos by 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene through the JAK-STAT and NOTCH signaling pathways.

1,1-Dichloro-2,2-bis(p-chlorophenyl)ethylene (p,p'-DDE) is the primary molecular metabolite of 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT), a pesticide used to control the spread of dengue and Zika viruses, and can be detected in the majority of human blood samples. However, whether p,p'-DDE affects embryonic cardiac development remains unknown. This study aimed to explore the cardiotoxicity of p,p'-DDE and its potential mechanisms of action in zebrafish embryos. We demonstrated for the first time that zebrafish embryos exposed to p,p'-DDE exhibited cardiac development abnormalities, including morphological and functional abnormalities, such as pericardial edema, thinning of the ventricular wall, reduced erythrocyte intensity, and increased heart rate. The results of Kyoto Encyclopedia of Genes and Genomes analysis of differentially expressed genes and qRT-PCR showed that JAK-STAT-related genes (il17d, socs3a, and bcl2b) and Notch-related genes (notch1a, notch1b, bmp10, efnb2a, tbx2b, and tbx5a) were altered after p,p'-DDE treatment, leading to reduced proliferation and increased apoptosis of cardiomyocytes and irregular formation of ventricular and abnormal atrioventricular junctions. These results were verified using acridine orange staining, 5-ethynyl-2'-deoxyuridine assays, and whole-mount in situ hybridization. Our research suggests that p,p'-DDE affects cardiac development in zebrafish embryos and that its cardiotoxicity may be associated with the JAK-STAT and Notch signaling pathways. Our findings may provide the basis for future population-based cohort studies.