RESUMO
The appearance of human immunodeficiency virus type 1 (HIV-1) plasma viremia is associated with progression to symptomatic disease and CD4+ T cell depletion. To locate the source of systemic viremia, this study employed a novel method to trace HIV-1 infection in vivo. We created JRCSFξnef, a pool of infectious HIV-1 (strain JR-CSF) with highly mutated nef gene regions by random mutagenesis PCR and infected this mutated virus pool into both Jurkat-CCR5 cells and hematopoietic stem cell-transplanted humanized mice. Infection resulted in systemic plasma viremia in humanized mice and viral RNA sequencing helped us to identify multiple lymphoid organs such as spleen, lymph nodes, and bone marrow but not peripheral blood cells as the source of systemic viremia. Our data suggest that this method could be useful for the tracing of viral trafficking in vivo.
Assuntos
Infecções por HIV , HIV-1 , Viremia/diagnóstico , Animais , Linfócitos T CD4-Positivos , Infecções por HIV/diagnóstico , Infecções por HIV/virologia , HIV-1/genética , Humanos , Células Jurkat , Camundongos , RNA Viral , Viremia/virologia , Replicação Viral , Produtos do Gene nef do Vírus da Imunodeficiência HumanaRESUMO
Gene expression aberration is a hallmark of cancers, but the mechanisms underlying such aberrations remain unclear. Human endogenous retroviruses (HERVs) are genomic repetitive elements that potentially function as enhancers. Since numerous HERVs are epigenetically activated in tumors, their activation could cause global gene expression aberrations in tumors. Here, we show that HERV activation in tumors leads to the up-regulation of hundreds of transcriptional suppressors, namely, Krüppel-associated box domain-containing zinc-finger family proteins (KZFPs). KZFP genes are preferentially encoded nearby the activated HERVs in tumors and transcriptionally regulated by these adjacent HERVs. Increased HERV and KZFP expression in tumors was associated with better disease conditions. Increased KZFP expression in cancer cells altered the expression of genes related to the cell cycle and cell-matrix adhesion and suppressed cellular growth, migration, and invasion abilities. Our data suggest that HERV activation in tumors drives the synchronized elevation of KZFP expression, presumably leading to tumor suppression.
Assuntos
Retrovirus Endógenos , Neoplasias , Retrovirus Endógenos/genética , Humanos , Neoplasias/genética , Ativação Transcricional , Zinco , Dedos de ZincoRESUMO
APOBEC3 (A3) family proteins are DNA cytosine deaminases recognized for contributing to HIV-1 restriction and mutation. Prior studies have demonstrated that A3D, A3F, and A3G enzymes elicit a robust anti-HIV-1 effect in cell cultures and in humanized mouse models. Human A3H is polymorphic and can be categorized into three phenotypes: stable, intermediate, and unstable. However, the anti-viral effect of endogenous A3H in vivo has yet to be examined. Here we utilize a hematopoietic stem cell-transplanted humanized mouse model and demonstrate that stable A3H robustly affects HIV-1 fitness in vivo. In contrast, the selection pressure mediated by intermediate A3H is relaxed. Intriguingly, viral genomic RNA sequencing reveled that HIV-1 frequently adapts to better counteract stable A3H during replication in humanized mice. Molecular phylogenetic analyses and mathematical modeling suggest that stable A3H may be a critical factor in human-to-human viral transmission. Taken together, this study provides evidence that stable variants of A3H impose selective pressure on HIV-1.
Assuntos
Aminoidrolases/genética , Citosina Desaminase/genética , Infecções por HIV/virologia , HIV-1/fisiologia , Produtos do Gene vif do Vírus da Imunodeficiência Humana/genética , Desaminases APOBEC , Aminoidrolases/metabolismo , Animais , Citidina Desaminase , Citosina Desaminase/metabolismo , Modelos Animais de Doenças , Células HEK293 , Infecções por HIV/transmissão , HIV-1/genética , Humanos , Camundongos , Camundongos Knockout , Modelos Genéticos , Mutação , Filogenia , RNA Viral/química , RNA Viral/genética , Análise de Sequência de RNA , Replicação ViralRESUMO
Apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3) proteins are mammalian-specific cellular deaminases and have a robust ability to restrain lentivirus replication. To antagonize APOBEC3-mediated antiviral action, lentiviruses have acquired viral infectivity factor (Vif) as an accessory gene. Mammalian APOBEC3 proteins inhibit lentiviral replication by enzymatically inserting G-to-A hypermutations in the viral genome, whereas lentiviral Vif proteins degrade host APOBEC3 via the ubiquitin/proteasome-dependent pathway. Recent investigations provide evidence that lentiviral vif genes evolved to combat mammalian APOBEC3 proteins. In corollary, mammalian APOBEC3 genes are under Darwinian selective pressure to escape from antagonism by Vif. Based on these observations, it is widely accepted that lentiviral Vif and mammalian APOBEC3 have co-evolved and this concept is called an "evolutionary arms race." This review provides a comprehensive summary of current knowledge with respect to the evolutionary dynamics occurring at this pivotal host-virus interface.
Assuntos
Citidina Desaminase/genética , Citosina Desaminase/genética , Evolução Molecular , Genes vif , Lentivirus/genética , Desaminases APOBEC , Animais , Citidina Desaminase/metabolismo , Citosina Desaminase/metabolismo , HIV-1 , Interações Hospedeiro-Patógeno , Humanos , Mamíferos/virologia , Seleção Genética , Produtos do Gene vif do Vírus da Imunodeficiência Humana/genéticaRESUMO
Squamous cell esophageal cancer presents a significant health burden in many developing countries around the world. In South Africa, this disease is one of the most common causes of cancer-related deaths in black males. Because this cancer is only modestly responsive to available chemotherapeutic agents, there is a need to develop more effective therapeutic agents for this cancer. Marine organisms are currently regarded as a promising source of unique bioactive molecules because they display a rich diversity of secondary metabolites. Some of these compounds have significant anticancer activity, with a few of these currently in phase I and II clinical trials. We report here an ongoing program to screen marine organisms collected from subtidal benthic communities off the coast of southern Africa for activity against cultured esophageal cancer cells. Of the 137 extracts tested, 2.2% displayed high activity (score = 3) and 11.7% displayed moderate activity (score = 2) against cultured esophageal cancer cells. Our results suggest that sponges had a higher hit rate (21.9%) than ascidians (7.1%). Using activity-directed purification, seven previously described compounds and four novel compounds, with varying activity against esophageal cancer cell lines, were isolated from the sponges Axinella weltneri, Aplysilla sulphurea, and Strongylodesma aliwaliensis. The results of this study suggest that subtidal benthic marine organisms collected off the coast of southern Africa hold potential for identifying possible drug leads for the development of agents with activity against esophageal cancer.