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1.
Nature ; 620(7976): 1025-1030, 2023 Aug.
Article in English | MEDLINE | ID: mdl-37532928

ABSTRACT

HIV-1 remains a global health crisis1, highlighting the need to identify new targets for therapies. Here, given the disproportionate HIV-1 burden and marked human genome diversity in Africa2, we assessed the genetic determinants of control of set-point viral load in 3,879 people of African ancestries living with HIV-1 participating in the international collaboration for the genomics of HIV3. We identify a previously undescribed association signal on chromosome 1 where the peak variant associates with an approximately 0.3 log10-transformed copies per ml lower set-point viral load per minor allele copy and is specific to populations of African descent. The top associated variant is intergenic and lies between a long intergenic non-coding RNA (LINC00624) and the coding gene CHD1L, which encodes a helicase that is involved in DNA repair4. Infection assays in iPS cell-derived macrophages and other immortalized cell lines showed increased HIV-1 replication in CHD1L-knockdown and CHD1L-knockout cells. We provide evidence from population genetic studies that Africa-specific genetic variation near CHD1L associates with HIV replication in vivo. Although experimental studies suggest that CHD1L is able to limit HIV infection in some cell types in vitro, further investigation is required to understand the mechanisms underlying our observations, including any potential indirect effects of CHD1L on HIV spread in vivo that our cell-based assays cannot recapitulate.


Subject(s)
DNA Helicases , DNA-Binding Proteins , Genetic Variation , HIV Infections , HIV-1 , Viral Load , Humans , Cell Line , DNA Helicases/genetics , DNA Helicases/metabolism , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , HIV Infections/genetics , HIV-1/growth & development , HIV-1/physiology , Viral Load/genetics , Africa , Chromosomes, Human, Pair 1/genetics , Alleles , RNA, Long Noncoding/genetics , Virus Replication
3.
RNA Biol ; 18(sup1): 148-156, 2021 10 15.
Article in English | MEDLINE | ID: mdl-34541994

ABSTRACT

Recently published transcriptomic data of the SARS-CoV-2 coronavirus show that there is a large variation in the frequency and steady state levels of subgenomic mRNA sequences. This variation is derived from discontinuous subgenomic RNA synthesis, where the polymerase switches template from a 3' proximal genome body sequence to a 5' untranslated leader sequence. This leads to a fusion between the common 5' leader sequence and a 3' proximal body sequence in the RNA product. This process revolves around a common core sequence (CS) that is present at both the template sites that make up the fusion junction. Base-pairing between the leader CS and the nascent complementary minus strand body CS, and flanking regions (together called the transcription regulating sequence, TRS) is vital for this template switching event. However, various factors can influence the site of template switching within the same TRS duplex. Here, we model the duplexes formed between the leader and complementary body TRS regions, hypothesizing the role of the stability of the TRS duplex in determining the major sites of template switching for the most abundant mRNAs. We indicate that the stability of secondary structures and the speed of transcription play key roles in determining the probability of template switching in the production of subgenomic RNAs. We speculate on the effect of reported variant nucleotide substitutions on our models.


Subject(s)
Gene Expression Regulation, Viral , RNA, Viral/chemistry , SARS-CoV-2/chemistry , Transcription, Genetic , Mutation , Nucleic Acid Conformation , RNA Stability , SARS-CoV-2/classification , SARS-CoV-2/genetics
4.
Viruses ; 13(4)2021 03 31.
Article in English | MEDLINE | ID: mdl-33807175

ABSTRACT

Type I interferons (IFNs) are produced by most cells in response to virus infection and stimulate a program of anti-viral gene expression in neighboring cells to suppress virus replication. Type III IFNs have similar properties, however their effects are limited to epithelial cells at mucosal surfaces due to restricted expression of the type III IFN receptor. Rotavirus (RV) replicates in intestinal epithelial cells that respond predominantly to type III IFNs, and it has been shown that type III rather than type I IFNs are important for controlling RV infections in vivo. The RV NSP1 protein antagonizes the host type I IFN response by targeting IRF-3, IRF-5, IRF-7, or ß-TrCP for proteasome-mediated degradation in a strain-specific manner. Here we provide the first demonstration that NSP1 proteins from several human and animal RV strains antagonize type III as well as type I IFN induction. We also show that NSP1 is a potent inhibitor of IRF-1, a previously undescribed property of NSP1 which is conserved among human and animal RVs. Interestingly, all NSP1 proteins were substantially more effective inhibitors of IRF-1 than either IRF-3 or IRF-7 which has significance for evasion of basal anti-viral immunity and type III IFN induction in the intestinal epithelium.


Subject(s)
Epithelial Cells/virology , Interferon Type I/antagonists & inhibitors , Interferons/antagonists & inhibitors , Rotavirus/immunology , Viral Nonstructural Proteins/genetics , Viral Nonstructural Proteins/immunology , Animals , Epithelial Cells/immunology , HEK293 Cells , Humans , Interferon Regulatory Factor-1/antagonists & inhibitors , Interferon Regulatory Factor-1/immunology , Interferon Type I/immunology , Interferons/immunology , Intestines/cytology , Rotavirus/chemistry , Rotavirus/isolation & purification
5.
ACS Nano ; 14(10): 12271-12280, 2020 10 27.
Article in English | MEDLINE | ID: mdl-33052643

ABSTRACT

Biosensing plays vital roles in multiple fields, including healthcare monitoring, drug screening, disease diagnosis, and environmental pollution control. In recent years, transistor-based devices have been considered to be valid platforms for fast, low-cost sensing of diverse analytes. Without additional functionalization, however, these devices lack selectivity; several strategies have been developed for the direct immobilization of bioreceptors on the transistor surface to improve detection capabilities. In this scenario, organic transistors have gained attention for their abilities to be coupled to biological systems and to detect biomolecules. In this Perspective, we discuss recent developments in organic-transistor-based biosensors, highlighting how their coupling with artificial membranes provides a strategy to improve sensitivity and selectivity in biosensing applications. Looking at future applications, this class of biosensors represents a breakthrough starting point for implementing multimodal high-throughput screening platforms.


Subject(s)
Biosensing Techniques , Membranes, Artificial , Organic Chemicals , Transistors, Electronic
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