Virology
Abstract
BACKGROUND. Epstein-Barr virus (EBV) is associated with nasopharyngeal carcinoma (NPC), but the existence of NPC protective antibody against EBV-associated antigens remains inconclusive. METHODS. NPC cases and matched controls were identified from prospective cohorts comprising 75,481 participants in southern China. ELISA and conditional logistic regression were applied to assess effects of gp42-IgG on NPC. The expression of HLA-II, the gp42 receptor, in nasopharyngeal atypical dysplasia and its impact on EBV infecting epithelial cells were evaluated. FINDINGS. gp42-IgG titers were significantly lower in NPC cases compared to controls across various follow-up years before NPC diagnosis (P<0.05). Individuals in the highest quartile of gp42-IgG titers had a 71% NPC risk reduction comparing to those in the lowest quartile (odds ratios [OR]Q4vsQ1=0.29, 95% confidence intervals [CIs]=0·15 to 0·55, P<0.001). Each unit antibody titer increase was associated with 34% lower risk of NPC (OR=0.66, 95% CI=0.54 to 0.81, Ptrend <0.001). Their protective effect was observed in cases diagnosed ≥5 years, 1-5 years and <1 year after blood collection (P<0.05). HLA-II expression was detected in 13 of 27 nasopharyngeal atypical dysplasia and its overexpression substantially promoted epithelial-cell-origin EBV infection. CONCLUSION. Elevated EBV gp42-IgG titers can reduce NPC risk, indicating gp42 as a potential EBV prophylactic vaccine design target. TRIAL REGISTRATION. NCT00941538, NCT02501980, ChiCTR2000028776, ChiCTR2100041628. FUNDING. Noncommunicable Chronic Diseases-National Science and Technology Major Project, National Natural Science Foundation of China, Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program, Central Financial Transfer Payment Projects of the Chinese Government, Cancer Research Grant of Zhongshan City.
Authors
Xiang-Wei Kong, Guo-Long Bu, Hua Chen, Yu-Hua Huang, Zhiwei Liu, Yin-Feng Kang, Yan-Cheng Li, Xia Yu, Biao-Hua Wu, Zi-Qian Li, Xin-Chun Chen, Shang-Hang Xie, Dong-Feng Lin, Tong Li, Shu-Mei Yan, Run-Kun Han, Nan Huang, Qian-Yu Wang, Yan Li, Ao Zhang, Qian Zhong, Xiao-Ming Huang, Weimin Ye, Ming-Fang Ji, Yong-Lin Cai, Su-Mei Cao, Mu-Sheng Zeng
Abstract
The function of the spike protein N terminal domain (NTD) in coronavirus (CoV) infections is poorly understood. However, some rare antibodies that target the SARS-CoV-2 NTD potently neutralize the virus. This finding suggests the NTD may contribute in part to protective immunity. Pan-sarbecovirus antibodies are desirable for broad protection, but the NTD region of SARS-CoV and SARS-CoV-2 exhibit a high level of sequence divergence, and therefore, cross-reactive NTD-specific antibodies are unexpected, and there is no structure of a SARS-CoV NTD-specific antibody in complex with NTD. Here we report a monoclonal antibody COV1-65 encoded by the IGHV1-69 gene that recognizes the NTD of SARS-CoV S protein. A prophylaxis study showed the MAb COV1-65 prevented disease when administered before SARS-CoV challenge of BALB/c mice, an effect that requires intact Fc effector functions for optimal protection in vivo. The footprint on the S protein of COV1-65 is near to functional components of the S2 fusion machinery, and the selection of COV1-65 escape mutant viruses identified critical residues Y886H and Q974H, which likely affect the epitope through allosteric effects. Structural features of the mAb COV1-65-SARS-CoV antigen interaction suggest critical antigenic determinants that should be considered in the rational design of sarbecovirus vaccine candidates.
Authors
Naveenchandra Suryadevara, Nurgun Kose, Sandhya Bangaru, Elad Binshtein, Jennifer Munt, David R. Martinez, Alexandra Schäfer, Luke Myers, Trevor D. Scobey, Robert H. Carnahan, Andrew B. Ward, Ralph S. Baric, James E. Crowe Jr.
Abstract
Authors
Hannes Vietzen, Laura M. Kühner, Sarah M. Berger, Philippe L. Furlano, Gabriel Bsteh, Thomas Berger, Paulus Rommer, Elisabeth Puchhammer-Stöckl
Abstract
Despite effective antiretroviral therapy (ART), persons living with HIV (PWH) harbor reservoirs of persistently infected CD4+ cells, which constitute a barrier to cure. Initiation of ART during acute infection reduces the size of the HIV reservoir, and we hypothesized that in addition, it would favor integration of proviruses in HIV-specific CD4+ T cells, while initiation of ART during chronic HIV infection would favor relatively more proviruses in herpesvirus-specific cells. We further hypothesized that proviruses in acute-ART-initiators would be integrated into antiviral genes, whereas integration sites in chronic-ART-initiators would favor genes associated with cell proliferation and exhaustion. We found the HIV DNA distribution across HIV-specific vs. herpesvirus-specific CD4+ T cells was as hypothesized. HIV integration sites (IS) in acute-ART-initiators were significantly enriched in gene sets controlling lipid metabolism and HIF-1α-mediated hypoxia, both metabolic pathways active in early HIV infection. Persistence of these infected cells during prolonged ART suggests a survival advantage. IS in chronic-ART-initiators were enriched in a gene set controlling EZH2 histone methylation; and methylation has been associated with diminished LTR transcription. These differences we found in antigen specificities and IS distributions within HIV-infected cells might be leveraged in designing cure strategies tailored to the timing of ART initiation.
Authors
Jaimy Joy, Ana L. Gervassi, Lennie Chen, Brent Kirshenbaum, Sheila Styrchak, Daisy Ko, Sherry McLaughlin, Danica Shao, Ewelina Kosmider, Paul T. Edlefsen, Janine Maenza, Ann C. Collier, James I. Mullins, Helen Horton, Lisa M. Frenkel
Abstract
Background: Persistent controllers (PC) maintain antiretroviral-free HIV-1 control indefinitely over time while transient controllers (TC) eventually lose virological control. It is essential to characterize the quality of the HIV reservoir of these phenotypes to identify the factors that lead to HIV progression and to open new avenues in HIV cure strategies. Methods: The characterization of HIV-1 reservoir, from peripheral blood mononuclear cells, was performed using next-generation sequencing techniques, such as full-length individual and matched integration site proviral sequencing (FLIP-seq; MIP-seq). Results: PC and TC before losing virological control, presented significantly lower total, intact and defective proviruses compared to participants on antiretroviral therapy (ART). No differences were found in total and defective proviruses between PC and TC. However, intact provirus levels were lower in PC compared to TC, being the intact/defective HIV-DNA ratio significantly higher in TC. Clonally expanded intact proviruses were found only in PC and located in centromeric satellite DNA or zinc-finger genes, both associated with heterochromatin features. In contrast, sampled intact proviruses were located in permissive genic euchromatic positions in TC. Conclusions: These results suggest the need for, and can give guidance to the design of, future research to identify a distinct proviral landscape that may be associated with the persistent control of HIV-1 without ART. Funding: Instituto de Salud Carlos III (FI17/00186, FI19/00083, MV20/00057 PI18/01532, PI19/01127 and PI22/01796), Consejería de Economía, Conocimiento, Empresas y Universidad, Junta de Andalucía (PI20/1276), Gilead Fellowships (GLD22/00147) and I+D+iFEDER Andalucía 2014-2020 (US-1380938).
Authors
Carmen Gasca-Capote, Xiaodong Lian, Ce Gao, Isabelle C. Roseto, María Reyes Jiménez-León, Gregory Gladkov, María Inés Camacho-Sojo, Alberto Pérez-Gómez, Isabel Gallego, Luis E. Lopez-Cortes, Sara Bachiller, Joana Vitalle, Mohammed Rafii-El-Idrissi Benhnia, Francisco J. Ostos, Antonio R. Collado-Romacho, Jesús Santos, Rosario Palacios, Cristina Gomez-Ayerbe, Leopoldo Muñoz-Medina, Andrés Ruiz-Sancho, Mario Frias, Antonio Rivero-Juarez, Cristina Roca-Oporto, Carmen Hidalgo-Tenorio, Anna Rull, Julian Olalla, Miguel A. Lopez-Ruz, Francesc Vidal, Consuelo Viladés, Andrea Mastrangelo, Matthias Cavassini, Nuria Espinosa, Matthieu Perreau, Joaquin Peraire, Antonio Rivero, Luis F. López-Cortes, Mathias Lichterfeld, Xu G. Yu, Ezequiel Ruiz-Mateos
Abstract
Authors
Amanda Macamo, Jan Beckervordersandforth, Axel zur Hausen
Abstract
Authors
Vaidya Govindarajan, Jay Chandar, Avindra Nath, Ashish H. Shah
Abstract
Virophagy, the selective autophagosomal engulfment and lysosomal degradation of viral components, is crucial for neuronal cell survival and antiviral immunity. However, the mechanisms leading to viral antigen recognition and capture by autophagic machinery remain poorly understood. Here, we identified cyclin-dependent kinase-like 5 (CDKL5), known to function in neurodevelopment, as an essential regulator of virophagy. Loss of function mutations in CDKL5 are associated with a severe neurodevelopmental encephalopathy. We found deletion of CDKL5 or expression of a clinically-relevant pathogenic mutant of CDKL5 reduced virophagy of Sindbis virus (SINV), a neurotropic RNA virus, and increased intracellular accumulation of SINV capsid protein aggregates and cellular cytotoxicity. CDKL5 knockout mice displayed increased viral antigen accumulation and neuronal cell death after SINV infection and enhanced lethality after infection with several neurotropic viruses. Mechanistic studies demonstrated that CDKL5 directly binds the canonical selective autophagy receptor p62 and phosphorylates p62 at T269/S272 to promote its interaction with viral capsid aggregates. We found that CDKL5-mediated phosphorylation of p62 facilitated the formation of large p62 inclusion bodies that captured viral capsids to initiate capsid targeting to autophagic machinery. Overall, these findings identify a cell-autonomous innate immune mechanism for autophagy activation to clear intracellular toxic viral protein aggregates during infection.
Authors
Josephine W. Thinwa, Zhongju Zou, Emily Parks, Salwa Sebti, Kelvin K. Hui, Yongjie Wei, Mohammad Goodarzi, Vibha Singh, Greg Urquhart, Jenna L. Jewell, Julie K. Pfeiffer, Beth Levine, Tiffany A. Reese, Michael U. Shiloh
Abstract
Many cancers harbour homologous recombination defect (HRD), the therapeutic target being successfully applied in treating breast/ovarian cancer via synthetic lethality. However, canonical HRD caused by BRCAness mutations is not explicit in liver cancer. Here we report a subtype of HRD caused by the perturbation of a proteasome variant (CDW19S) in hepatitis B virus (HBV) bearing cells. This amalgamate protein complex contained the 19S proteasome decorated with CRL4WDR70 ubiquitin ligase, and assembled at broken chromatin in a PSMD4Rpn10 and ATM- MDC1-RNF8 dependent manner. CDW19S promoted DNA end processing via segregated modules that promote nuclease activities of MRE11 and EXO1. Contrarily, a proteasomal component, ADRM1Rpn13, inhibited resection and was removed by CRL4WDR70-catalysed ubiquitination upon commitment of extensive resection. HBx interfered with ADRM1Rpn13 degradation, leading to the imposition of ADRM1Rpn13-dependent resection barrier and consequent viral HRD subtype distinguishable from that caused by BRCA1 defect. Finally, we demonstrated that viral HRD in HBV-associated hepatocellular carcinoma (HBVHCC) can be exploited to restrict tumor progression. Our work clarifies the underlying mechanism of a viral-induced HRD subtype.
Authors
Ming Zeng, Zizhi Tang, Laifeng Ren, Haibin Wang, Xiaojun Wang, Wenyuan Zhu, Xiaobing Mao, Zeyang Li, Xianming Mo, Jun Chen, Junhong Han, Daochun Kong, Jianguo Ji, Antony M. Carr, Cong Liu
Abstract
Targeting host factors exploited by multiple viruses could offer broad-spectrum solutions for pandemic preparedness. Seventeen candidates targeting diverse functions emerged in a screen of 4,413 compounds for SARS-CoV-2 inhibitors. We demonstrated that lapatinib and other approved inhibitors of the ErbB family receptor tyrosine kinases suppress replication of SARS-CoV-2, Venezuelan equine encephalitis virus (VEEV), and other emerging viruses with a high barrier to resistance. Lapatinib suppressed SARS-CoV-2 entry and later stages of the viral life cycle and showed synergistic effect with the direct-acting antiviral nirmatrelvir. We discovered that ErbB1, 2 and 4 bind SARS-CoV-2 S1 protein and regulate viral and ACE2 internalization, and they are required for VEEV infection. In human lung organoids, lapatinib protected from SARS-CoV-2-induced activation of ErbB-regulated pathways implicated in non-infectious lung injury, pro-inflammatory cytokine production, and epithelial barrier injury. Lapatinib suppressed VEEV replication, cytokine production and disruption of the blood-brain barrier integrity in microfluidic-based human neurovascular units, and reduced mortality in a lethal infection murine model. We validated lapatinib-mediated inhibition of ErbB activity as an important mechanism of antiviral action. These findings reveal regulation of viral replication, inflammation, and tissue injury via ErbBs and establish a proof-of-principle for a repurposed, ErbB-targeted approach to combat emerging viruses.
Authors
Sirle Saul, Marwah Karim, Luca Ghita, Pei-Tzu Huang, Winston Chiu, Verónica Durán, Chieh-Wen Lo, Sathish Kumar, Nishank Bhalla, Pieter Leyssen, Farhang Alem, Niloufar A. Boghdeh, Do HoangNhu Tran, Courtney A. Cohen, Jacquelyn A. Brown, Kathleen E. Huie, Courtney Tindle, Mamdouh Sibai, Chengjin Ye, Ahmed Magdy Khalil, Kevin Chiem, Luis Martinez-Sobrido, John M. Dye, Benjamin A. Pinsky, Pradipta Ghosh, Soumita Das, David E. Solow-Cordero, Jing Jin, John P. Wikswo, Dirk Jochmans, Johan Neyts, Steven De Jonghe, Aarthi Narayanan, Shirit Einav
No posts were found with this tag.
Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)