Abstract:
:Vif counteracts the host restriction factor APOBEC3G (A3G) and other APOBEC3s by preventing the incorporation of A3G into progeny virions. We previously identified Vif mutants with a dominant-negative (D/N) phenotype that interfered with the function of wild-type Vif, inhibited the degradation of A3G, and reduced the infectivity of viral particles by increased packaging of A3G. However, the mechanism of interference remained unclear, in particular since all D/N Vif mutants were unable to bind Cul5 and some mutants additionally failed to bind A3G, ruling out competitive binding to A3G or the E3 ubiquitin ligase complex as the sole mechanism. The goal of the current study was to revisit the mechanism of D/N interference by Vif mutants and analyze the possible involvement of core binding factor beta (CBFβ) in this process. We found a clear correlation of D/N properties of Vif mutants with their ability to engage CBFβ. Only mutants that retained the ability to bind CBFβ exhibited the D/N phenotype. Competition studies revealed that D/N Vif mutants directly interfered with the association of CBFβ and wild-type Vif. Furthermore, overexpression of CBFβ counteracted the interference of D/N Vif mutants with A3G degradation by wild-type Vif. Finally, overexpression of Runx1 mimicked the effect of D/N Vif mutants and inhibited the degradation of A3G by wild-type Vif. Taken together, we identified CBFβ as the key player involved in D/N interference by Vif.IMPORTANCE Of all the accessory proteins encoded by HIV-1 and other primate lentiviruses, Vif has arguably the strongest potential as a target for antiviral therapy. This conclusion is based on the observation that replication of HIV-1 in vivo is critically dependent on Vif. Thus, inhibiting the function of Vif via small-molecule inhibitors or other approaches has significant therapeutic potential. We previously identified dominant-negative (D/N) Vif variants whose expression interferes with the function of virus-encoded wild-type Vif. We now show that D/N interference involves competitive binding of D/N Vif variants to the transcriptional cofactor core binding factor beta (CBFβ), which is expressed in cells in limiting quantities. Overexpression of CBFβ neutralized the D/N phenotype of Vif. In contrast, overexpression of Runx1, a cellular binding partner of CBFβ, phenocopied the D/N Vif phenotype by sequestering endogenous CBFβ. Thus, our results provide proof of principle that D/N Vif variants could have therapeutic potential.
journal_name
J Viroljournal_title
Journal of virologyauthors
Miyagi E,Welbourn S,Sukegawa S,Fabryova H,Kao S,Strebel Kdoi
10.1128/JVI.01708-19subject
Has Abstractpub_date
2020-03-17 00:00:00issue
7eissn
0022-538Xissn
1098-5514pii
JVI.01708-19journal_volume
94pub_type
杂志文章abstract::Equine herpesvirus 1 (EHV1) replicates in the respiratory epithelium and disseminates through the body via a cell-associated viremia in leukocytes, despite the presence of neutralizing antibodies. "Hijacked" leukocytes, previously identified as monocytic cells and T lymphocytes, transmit EHV1 to endothelial cells of t...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.02098-18
更新日期:2019-03-21 00:00:00
abstract::Epstein-Barr Virus (EBV) generates a variety of viral microRNAs (miRNAs) by processing the BHRF1 and BamHI A rightward (BART) transcripts. BART miRNAs are expressed in all cells latently infected with EBV, but the functions of most BART miRNAs remain unknown. The results of a cell proliferation assay revealed that miR...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.03159-12
更新日期:2013-07-01 00:00:00
abstract::Cas-Br-M is an ecotropic murine leukemia virus (MuLV) of wild-mouse origin that causes neurogenic hind-limb paralysis. By virtue of its N-tropism, the virus replicates well in tissues of mice bearing the n but not the b allele at the Fv-1 locus. To determine if different Fv-1n strains of mice were equally susceptible ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.53.1.40-43.1985
更新日期:1985-01-01 00:00:00
abstract::All presently available replication-competent proviral clones of human immunodeficiency virus type 1 (HIV-1) are derived from cell culture-amplified virus. Since tissue culture is highly selective for viral strains with an in vitro growth advantage, such clones may not be representative of the biologically relevant vi...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.65.8.3973-3985.1991
更新日期:1991-08-01 00:00:00
abstract::Our previous studies have shown that targeting DNA vaccine-encoded major histocompatibility complex class I epitopes to the proteasome enhanced CD8(+) T-cell induction and protection against lymphocytic choriomeningitis virus (LCMV) challenge. Here, we expand these studies to evaluate CD4(+) T-cell responses induced b...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.75.21.10421-10430.2001
更新日期:2001-11-01 00:00:00
abstract::Foxp3(+) CD4(+) regulatory T cells (Tregs) represent a highly suppressive T cell subset with well-characterized immunosuppressive effects during immune homeostasis and chronic infections, although the role of these cells in acute viral infections is poorly understood. The present study sought to examine the induction ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.05685-11
更新日期:2012-03-01 00:00:00
abstract::Human cytomegalovirus-induced DNA polymerase and cellular DNA polymerase alpha were purified by successive chromatography on DEAE-cellulose, phosphocellulose, heparin agarose, and single-stranded DNA agarose columns. The purified virus-induced DNA polymerase was resolved to consist of two polypeptides corresponding to...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.56.3.846-851.1985
更新日期:1985-12-01 00:00:00
abstract::Mycophenolic acid (MPA), an inhibitor of IMP dehydrogenase, inhibits reovirus replication and viral RNA and protein production. In mouse L929 cells, antiviral effects were greatest at 30 microg of MPA/ml. At this dosage, MPA inhibited replication of reovirus strain T3D more than 1,000-fold and inhibited replication of...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.78.12.6171-6179.2004
更新日期:2004-06-01 00:00:00
abstract::Ovine herpesvirus 2 (OvHV-2) is a gammaherpesvirus in the genus Macavirus that is carried asymptomatically by sheep. Infection of poorly adapted animals with OvHV-2 results in sheep-associated malignant catarrhal fever, a fatal disease characterized by lymphoproliferation and vasculitis. There is no treatment or vacci...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.02454-16
更新日期:2017-02-28 00:00:00
abstract::Upon inoculation into AKR mice, mink cell focus-forming murine leukemia virus (MCF MLV) accelerates thymic lymphoma formation. During the preleukemic phase of disease, we observed the induction of apoptosis in thymic lymphocytes. A similar induction of apoptosis was observed for cultured mink epithelial cells after MC...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/jvi.78.10.5088-5096.2004
更新日期:2004-05-01 00:00:00
abstract::In less than 3 months after the first cases of swine origin 2009 influenza A (H1N1) virus infections were reported from Mexico, WHO declared a pandemic. The pandemic virus is antigenically distinct from seasonal influenza viruses, and the majority of human population lacks immunity against this virus. We have studied ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.01619-09
更新日期:2010-02-01 00:00:00
abstract:UNLABELLED:Human noroviruses are icosahedral single-stranded RNA viruses. The capsid protein is divided into shell (S) and protruding (P) domains, which are connected by a flexible hinge region. There are numerous genetically and antigenically distinct noroviruses, and the dominant strains evolve every other year. Vacc...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.03176-14
更新日期:2015-03-01 00:00:00
abstract::Among the numerous immunological abnormalities observed in chronically human immunodeficiency virus (HIV)-infected individuals, perturbations in memory CD4 T cells are thought to contribute specifically to disease pathogenesis. Among these, functional imbalances in the frequencies of T regulatory cells (Tregs) and int...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.02163-18
更新日期:2019-04-17 00:00:00
abstract::Growth kinetics in lymphocytic H9 and M8166 cells of two mutants of human immunodeficiency virus type 1 (HIV-1) with deleted gp41 cytoplasmic tails were examined. While the mutant viruses designated CTdel-44 and CTdel-144 were able to grow in M8166 cells, they were unable to grow in H9 cells. Transfection and single-r...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/jvi.74.10.4891-4893.2000
更新日期:2000-05-01 00:00:00
abstract::Small ruminants infected with peste des petits ruminants virus exhibit lesions typical of epithelial infection and necrosis. However, the only established host receptor for this virus is the immune cell marker signaling lymphocyte activation molecule (SLAM). We have confirmed that the ovine Nectin-4 protein, when over...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.02792-12
更新日期:2013-04-01 00:00:00
abstract::The polypeptide and glycoprotein compositions of the mouse mammary tumor virus virion from primary monolayer cultures of BALB/cfC3H mouse mammary tumor cells were studied by polyacrylamide gel electrophoresis by using internal and external labeling and Coomassie blue and periodic acid Schiff (PAS) staining. Twelve pol...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.13.2.411-418.1974
更新日期:1974-02-01 00:00:00
abstract::Astrovirus is one of the major causes of infant and childhood diarrhea worldwide. Our understanding of astrovirus pathogenesis trails behind our knowledge of its molecular and epidemiologic properties. Using a recently developed small-animal model, we investigated the mechanisms by which astrovirus induces diarrhea an...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/jvi.78.3.1564-1574.2004
更新日期:2004-02-01 00:00:00
abstract::BALB/c mice treated with pristane and Abelson virus have been used as an animal model system for the rapid induction of plasmacytomas. Myelomonocytic tumors with helper Moloney murine leukemia virus clonally inserted into the c-myb locus were observed in about 10% of pristane-primed BALB/c mice infected with Abelson v...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.61.12.3721-3725.1987
更新日期:1987-12-01 00:00:00
abstract::The intracellular assembly of the transmissible gastroenteritis coronavirus (TGEV) was studied in infected swine testis (ST) cells at different postinfection times by using ultrathin sections of conventionally embedded infected cells, freeze-substitution, and methods for detecting viral proteins and RNA at the electro...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.72.5.4022-4031.1998
更新日期:1998-05-01 00:00:00
abstract::A rapid assay for retroviral reverse transcriptase activity released into the culture medium by infected cells was developed. With the assay, 4,000 clonally infected cell lines could be tested in a few hours. We have adapted the assay for use as a screen for the detection of spontaneous viral mutants. Mutants of Molon...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.38.1.239-248.1981
更新日期:1981-04-01 00:00:00
abstract::The polycistronic P/C mRNA of Sendai virus is translated under cell-free conditions into five proteins (P, C', C, Y1, and Y2) from overlapping reading frames. In this study, we showed that in addition to the P, C', and C proteins, Y1 and Y2 were expressed by six different Sendai virus strains in infected cells. The Y ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.63.2.974-977.1989
更新日期:1989-02-01 00:00:00
abstract:UNLABELLED:Human T-cell lymphotropic virus type 1 (HTLV-1) and HTLV-2 encode auxiliary proteins that play important roles in viral replication, viral latency, and immune escape. The presence of auxiliary protein-encoding open reading frames (ORFs) in HTLV-3, the latest HTLV to be discovered, is unknown. Simian T-cell l...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.02150-14
更新日期:2015-01-15 00:00:00
abstract::Flavopiridol, roscovitine, and other inhibitors of Cyclin-Dependent Kinases (CDK) inhibit the replication of a variety of viruses in vitro while proving nontoxic in human clinical trials of their effects against cancer. Consequently, these and other Pharmacological CDK inhibitors (PCIs) have been proposed as potential...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.78.17.9352-9365.2004
更新日期:2004-09-01 00:00:00
abstract::In gene therapy, the innate immune system is a significant barrier to the effective application of adenovirus (Ad) vectors. In kidney epithelium-derived (REC) cells, serotype 5 Ad vectors induce the expression of the chemokine CXCL10 (IP-10), a response that is dependent on NFkappaB. Compared to the parental vector Ad...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.79.23.14507-14515.2005
更新日期:2005-12-01 00:00:00
abstract::Viral manipulation of cellular proteins allows viruses to suppress host defenses and generate infectious progeny. Due to the linear double-stranded DNA nature of the adenovirus genome, the cellular DNA damage response (DDR) is considered a barrier to successful infection. The adenovirus genome is packaged with protein...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.01089-17
更新日期:2017-09-27 00:00:00
abstract::We have used linker scanning and site-directed mutagenesis in an attempt to distinguish among the known functions of the duck hepatitis B virus large envelope protein, p36. We found that linker-encoded amino acid substitutions in at least one region of the pre-S envelope protein p36 produced defects in both the produc...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.68.7.4565-4571.1994
更新日期:1994-07-01 00:00:00
abstract::Type 1 human immunodeficiency viruses encoding mutated nef reading frames are 10- to 30-fold less infectious than are isogenic viruses in which the nef gene is intact. This defect in infectivity causes nef-negative viruses to grow at an attenuated rate in vitro. To investigate the mechanism of Nef-mediated enhancement...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.70.7.4283-4290.1996
更新日期:1996-07-01 00:00:00
abstract::A fragment of chicken DNA containing the left long terminal repeat of endogenous retrovirus ev-2 and flanking cellular sequences has been molecularly cloned and analyzed. Comparison with sequence data from the analogous regions of ev-1 and Rous-associated virus-0 viral DNA reveals similarities among flanking regions o...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.45.2.868-871.1983
更新日期:1983-02-01 00:00:00
abstract::Among the members of the paramyxovirus family, the transcription process and the components involved have been studied under in vitro conditions thus far. Here, we reexamined the function of the viral RNA-dependent RNA polymerase through infection studies with Sendai virus (SeV) N and P deletion (Delta) mutants. To el...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.00914-07
更新日期:2007-12-01 00:00:00
abstract::A protamine-like protein named P6.9 is thought to play a role in the condensation of genomes of the baculovirus Autographa californica multiple nucleopolyhedrovirus (AcMNPV) during an infection. Previous studies have shown that P6.9 is phosphorylated immediately upon synthesis and dephosphorylated upon the entry of th...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.00438-12
更新日期:2012-11-01 00:00:00