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  • Proceedings of the National Academy of Sciences  (6)
  • 1
    Online Resource
    Online Resource
    Broad-spectrum antiviral that interferes with de novo pyrimidine biosynthesis
    Proceedings of the National Academy of Sciences ; 2011
    In:  Proceedings of the National Academy of Sciences Vol. 108, No. 14 ( 2011-04-05), p. 5777-5782
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 108, No. 14 ( 2011-04-05), p. 5777-5782
    Abstract: Compound A3 was identified in a high-throughput screen for inhibitors of influenza virus replication. It displays broad-spectrum antiviral activity, and at noncytotoxic concentrations it is shown to inhibit the replication of negative-sense RNA viruses (influenza viruses A and B, Newcastle disease virus, and vesicular stomatitis virus), positive-sense RNA viruses (Sindbis virus, hepatitis C virus, West Nile virus, and dengue virus), DNA viruses (vaccinia virus and human adenovirus), and retroviruses (HIV). In contrast to mammalian cells, inhibition of viral replication by A3 is absent in chicken cells, which suggests species-specific activity of A3. Correspondingly, the antiviral activity of A3 can be linked to a cellular protein, dihydroorotate dehydrogenase (DHODH), which is an enzyme in the de novo pyrimidine biosynthesis pathway. Viral replication of both RNA and DNA viruses can be restored in the presence of excess uracil, which promotes pyrimidine salvage, or excess orotic acid, which is the product of DHODH in the de novo pyrimidine biosynthesis pathway. Based on these findings, it is proposed that A3 acts by depleting pyrimidine pools, which are crucial for efficient virus replication.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1101143108
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2011
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    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
    Location Call Number Limitation Availability
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    Online Resource
  • 2
    Online Resource
    Online Resource
    Red cells’ dynamic morphologies govern blood shear thinning under microcirculatory flow conditions
    Proceedings of the National Academy of Sciences ; 2016
    In:  Proceedings of the National Academy of Sciences Vol. 113, No. 47 ( 2016-11-22), p. 13289-13294
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 113, No. 47 ( 2016-11-22), p. 13289-13294
    Abstract: Blood viscosity decreases with shear stress, a property essential for an efficient perfusion of the vascular tree. Shear thinning is intimately related to the dynamics and mutual interactions of RBCs, the major component of blood. Because of the lack of knowledge about the behavior of RBCs under physiological conditions, the link between RBC dynamics and blood rheology remains unsettled. We performed experiments and simulations in microcirculatory flow conditions of viscosity, shear rates, and volume fractions, and our study reveals rich RBC dynamics that govern shear thinning. In contrast to the current paradigm, which assumes that RBCs align steadily around the flow direction while their membranes and cytoplasm circulate, we show that RBCs successively tumble, roll, deform into rolling stomatocytes, and, finally, adopt highly deformed polylobed shapes for increasing shear stresses, even for semidilute volume fractions of the microcirculation. Our results suggest that any pathological change in plasma composition, RBC cytosol viscosity, or membrane mechanical properties will affect the onset of these morphological transitions and should play a central role in pathological blood rheology and flow behavior.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1608074113
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2016
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
    Location Call Number Limitation Availability
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    Online Resource
  • 3
    Online Resource
    Online Resource
    Origin of the HIV-1 group O epidemic in western lowland gorillas
    Proceedings of the National Academy of Sciences ; 2015
    In:  Proceedings of the National Academy of Sciences Vol. 112, No. 11 ( 2015-03-17)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 112, No. 11 ( 2015-03-17)
    Abstract: HIV-1, the cause of AIDS, is composed of four phylogenetic lineages, groups M, N, O, and P, each of which resulted from an independent cross-species transmission event of simian immunodeficiency viruses (SIVs) infecting African apes. Although groups M and N have been traced to geographically distinct chimpanzee communities in southern Cameroon, the reservoirs of groups O and P remain unknown. Here, we screened fecal samples from western lowland ( n = 2,611), eastern lowland ( n = 103), and mountain ( n = 218) gorillas for gorilla SIV (SIVgor) antibodies and nucleic acids. Despite testing wild troops throughout southern Cameroon ( n = 14), northern Gabon ( n = 16), the Democratic Republic of Congo ( n = 2), and Uganda ( n = 1), SIVgor was identified at only four sites in southern Cameroon, with prevalences ranging from 0.8–22%. Amplification of partial and full-length SIVgor sequences revealed extensive genetic diversity, but all SIVgor strains were derived from a single lineage within the chimpanzee SIV (SIVcpz) radiation. Two fully sequenced gorilla viruses from southwestern Cameroon were very closely related to, and likely represent the source population of, HIV-1 group P. Most of the genome of a third SIVgor strain, from central Cameroon, was very closely related to HIV-1 group O, again pointing to gorillas as the immediate source. Functional analyses identified the cytidine deaminase APOBEC3G as a barrier for chimpanzee-to-gorilla, but not gorilla-to-human, virus transmission. These data indicate that HIV-1 group O, which spreads epidemically in west central Africa and is estimated to have infected around 100,000 people, originated by cross-species transmission from western lowland gorillas.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1502022112
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2015
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 4
    Online Resource
    Online Resource
    Cytidine deamination induced HIV-1 drug resistance
    Proceedings of the National Academy of Sciences ; 2008
    In:  Proceedings of the National Academy of Sciences Vol. 105, No. 14 ( 2008-04-08), p. 5501-5506
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 105, No. 14 ( 2008-04-08), p. 5501-5506
    Abstract: The HIV-1 Vif protein is essential for overcoming the antiviral activity of DNA-editing apolipoprotein B mRNA editing enzyme, catalytic polypeptide 3 (APOBEC3) cytidine deaminases. We show that naturally occurring HIV-1 Vif point mutants with suboptimal anti-APOBEC3G activity induce the appearance of proviruses with lamivudine (3TC) drug resistance-associated mutations before any drug exposure. These mutations, ensuing from cytidine deamination events, were detected in 〉 40% of proviruses with partially defective Vif mutants. Transfer of drug resistance from hypermutated proviruses via recombination allowed for 3TC escape under culture conditions prohibitive for any WT viral growth. These results demonstrate that defective hypermutated genomes can shape the phenotype of the circulating viral population. Partially active Vif alleles resulting in incomplete neutralization of cytoplasmic APOBEC3 molecules are directly responsible for the generation of a highly diverse, yet G-to-A biased, proviral reservoir, which can be exploited by HIV-1 to generate viable and drug-resistant progenies.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0710190105
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2008
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
    Location Call Number Limitation Availability
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  • 5
    Online Resource
    Online Resource
    IL-15 regulates susceptibility of CD4 + T cells to HIV infection
    Proceedings of the National Academy of Sciences ; 2018
    In:  Proceedings of the National Academy of Sciences Vol. 115, No. 41 ( 2018-10-09)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 115, No. 41 ( 2018-10-09)
    Abstract: HIV integrates into the host genome to create a persistent viral reservoir. Stimulation of CD4 + memory T lymphocytes with common γc-chain cytokines renders these cells more susceptible to HIV infection, making them a key component of the reservoir itself. IL-15 is up-regulated during primary HIV infection, a time when the HIV reservoir established. Therefore, we investigated the molecular and cellular impact of IL-15 on CD4 + T-cell infection. We found that IL-15 stimulation induces SAM domain and HD domain-containing protein 1 (SAMHD1) phosphorylation due to cell cycle entry, relieving an early block to infection. Perturbation of the pathways downstream of IL-15 receptor (IL-15R) indicated that SAMHD1 phosphorylation after IL-15 stimulation is JAK dependent. Treating CD4 + T cells with Ruxolitinib, an inhibitor of JAK1 and JAK2, effectively blocked IL-15–induced SAMHD1 phosphorylation and protected CD4 + T cells from HIV infection. Using high-resolution single-cell immune profiling using mass cytometry by TOF (CyTOF), we found that IL-15 stimulation altered the composition of CD4 + T-cell memory populations by increasing proliferation of memory CD4 + T cells, including CD4 + T memory stem cells (T SCM ). IL-15–stimulated CD4 + T SCM , harboring phosphorylated SAMHD1, were preferentially infected. We propose that IL-15 plays a pivotal role in creating a self-renewing, persistent HIV reservoir by facilitating infection of CD4 + T cells with stem cell-like properties. Time-limited interventions with JAK1 inhibitors, such as Ruxolitinib, should prevent the inactivation of the endogenous restriction factor SAMHD1 and protect this long-lived CD4 + T-memory cell population from HIV infection.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1806695115
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2018
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
    Location Call Number Limitation Availability
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    Online Resource
  • 6
    Online Resource
    Online Resource
    Influenza hemagglutinin-specific IgA Fc-effector functionality is restricted to stalk epitopes
    Proceedings of the National Academy of Sciences ; 2021
    In:  Proceedings of the National Academy of Sciences Vol. 118, No. 8 ( 2021-02-23)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 118, No. 8 ( 2021-02-23)
    Abstract: In this study, we utilized a panel of human immunoglobulin (Ig) IgA monoclonal antibodies isolated from the plasmablasts of eight donors after 2014/2015 influenza virus vaccination (Fluarix) to study the binding and functional specificities of this isotype. In this cohort, isolated IgA monoclonal antibodies were primarily elicited against the hemagglutinin protein of the H1N1 component of the vaccine. To compare effector functionalities, an H1-specific subset of antibodies targeting distinct epitopes were expressed as monomeric, dimeric, or secretory IgA, as well as in an IgG1 backbone. When expressed with an IgG Fc domain, all antibodies elicited Fc-effector activity in a primary polymorphonuclear cell-based assay which differs from previous observations that found only stalk-specific antibodies activate the low-affinity FcγRIIIa. However, when expressed with IgA Fc domains, only antibodies targeting the stalk domain showed Fc-effector activity in line with these previous findings. To identify the cause of this discrepancy, we then confirmed that IgG signaling through the high-affinity FcγI receptor was not restricted to stalk epitopes. Since no corresponding high-affinity Fcα receptor exists, the IgA repertoire may therefore be limited to stalk-specific epitopes in the context of Fc receptor signaling.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2018102118
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2021
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
    Location Call Number Limitation Availability
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