Abstract:
:Type I interferons (IFNs), including alpha IFN (IFN-α) and IFN-β, potently suppress HIV-1 replication by upregulating IFN-stimulated genes (ISGs). The viral capsid protein (CA) partly determines the sensitivity of HIV-1 to IFNs. However, it remains to be determined whether CA-related functions, including utilization of known host factors, reverse transcription, and uncoating, affect the sensitivity of HIV-1 to IFN-mediated restriction. Recently, we identified an HIV-1 CA variant that is unusually sensitive to IFNs. This variant, called the RGDA/Q112D virus, contains multiple mutations in CA: H87R, A88G, P90D, P93A, and Q112D. To investigate how an IFN-hypersensitive virus can evolve to overcome IFN-β-mediated blocks targeting the viral capsid, we adapted the RGDA/Q112D virus in IFN-β-treated cells. We successfully isolated IFN-β-resistant viruses which contained either a single Q4R substitution or the double amino acid change G94D/G116R. These two IFN-β resistance mutations variably changed the sensitivity of CA binding to human myxovirus resistance B (MxB), cleavage and polyadenylation specificity factor 6 (CPSF6), and cyclophilin A (CypA), indicating that the observed loss of sensitivity was not due to interactions with these known host CA-interacting factors. In contrast, the two mutations apparently functioned through distinct mechanisms. The Q4R mutation dramatically accelerated the kinetics of reverse transcription and initiation of uncoating of the RGDA/Q112D virus in the presence or absence of IFN-β, whereas the G94D/G116R mutations affected reverse transcription only in the presence of IFN-β, most consistent with a mechanism of the disruption of binding to an unknown IFN-β-regulated host factor. These results suggest that HIV-1 can exploit multiple, known host factor-independent pathways to avoid IFN-β-mediated restriction by altering capsid sequences and subsequent biological properties.IMPORTANCE HIV-1 infection causes robust innate immune activation in virus-infected patients. This immune activation is characterized by elevated levels of type I interferons (IFNs), which can block HIV-1 replication. Recent studies suggest that the viral capsid protein (CA) is a determinant for the sensitivity of HIV-1 to IFN-mediated restriction. Specifically, it was reported that the loss of CA interactions with CPSF6 or CypA leads to higher IFN sensitivity. However, the molecular mechanism of CA adaptation to IFN sensitivity is largely unknown. Here, we experimentally evolved an IFN-β-hypersensitive CA mutant which showed decreased binding to CPSF6 and CypA in IFN-β-treated cells. The CA mutations that emerged from this adaptation indeed conferred IFN-β resistance. Our genetic assays suggest a limited contribution of known host factors to IFN-β resistance. Strikingly, one of these mutations accelerated the kinetics of reverse transcription and uncoating. Our findings suggest that HIV-1 selected multiple, known host factor-independent pathways to avoid IFN-β-mediated restriction.
journal_name
J Viroljournal_title
Journal of virologyauthors
Sultana T,Mamede JI,Saito A,Ode H,Nohata K,Cohen R,Nakayama EE,Iwatani Y,Yamashita M,Hope TJ,Shioda Tdoi
10.1128/JVI.00986-19subject
Has Abstractpub_date
2019-11-13 00:00:00issue
23eissn
0022-538Xissn
1098-5514pii
JVI.00986-19journal_volume
93pub_type
杂志文章abstract::Clinical deterioration in human immunodeficiency virus type 1 (HIV-1) disease is associated with an increased viral burden in the peripheral blood and a loss of circulating CD4+ T cells. HIV-1 isolates obtained prior to this stage of disease often have a "slow-low," non-syncytium-inducing (NSI) phenotype, whereas thos...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.68.12.8188-8192.1994
更新日期:1994-12-01 00:00:00
abstract::Expression of the papillomavirus E4 protein correlates with the onset of viral DNA amplification. Using a mutant cottontail rabbit papillomavirus (CRPV) genome incapable of expressing the viral E4 protein, we have shown that E4 is required for the productive stage of the CRPV life cycle in New Zealand White and cotton...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/jvi.78.4.2142-2151.2004
更新日期:2004-02-01 00:00:00
abstract::Deletion mutants of simian virus 40 (SV40) with lesions at the three DdeI sites near the 3' end of the early region were constructed. Mutants with deletions at 0.203 and 0.219 map units (mu) which did not change the large T antigen reading frame were viable. This extends slightly the upstream boundary for the location...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.47.3.487-494.1983
更新日期:1983-09-01 00:00:00
abstract::Recent environmental and metagenomic studies have considerably increased the repertoire of archaeal viruses and suggested that they play important roles in nutrient cycling in the biosphere. However, very little is known about how they regulate their life cycles and interact with their hosts. Here, we report that the ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.00841-20
更新日期:2020-07-30 00:00:00
abstract::We determined the sequence of the gene for the virion transactivator protein Vmw65 of herpes simplex virus type 2 (HSV-2), strain 333. An analysis of the coding sequence revealed an overall high degree of primary sequence conservation (86%) relative to the HSV-1 protein, although the carboxy-terminal region which enco...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.65.12.6705-6713.1991
更新日期:1991-12-01 00:00:00
abstract::Propagation of the flavivirus tick-borne encephalitis virus in BHK-21 cells selected for mutations within the large surface glycoprotein E that increased the net positive charge of the protein. In the course of 16 independent experiments, 12 different protein E mutation patterns were identified. These were located in ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.75.12.5627-5637.2001
更新日期:2001-06-01 00:00:00
abstract::The internal hydrophobic sequence within the flaviviral capsid protein (protein C) plays an important role in the assembly of infectious virions. Here, this sequence was analyzed in a West Nile virus lineage I isolate (crow V76/1). An infectious cDNA clone was constructed and used to introduce deletions into the inter...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.02653-08
更新日期:2009-06-01 00:00:00
abstract::It was recently shown that the 7a protein of severe acute respiratory syndrome coronavirus induces biochemical changes associated with apoptosis. In this study, the mechanism by which the 7a protein induces apoptosis was examined. The 7a protein was tested for the ability to inhibit cellular gene expression because se...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.80.2.785-793.2006
更新日期:2006-01-01 00:00:00
abstract::Nucleotide sequence analysis of the long terminal repeat (LTR) of the integrated simian sarcoma virus showed that the simian sarcoma virus LTR comprised 504 nucleotides with an inverted repeat of seven bases at its 5' and 3' termini. At the site of simian sarcoma virus integration, cellular flanking sequences adjacent...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.42.3.1108-1113.1982
更新日期:1982-06-01 00:00:00
abstract::High rates of genetic variation ensure the survival of RNA viruses. Although this variation is thought to result from error-prone replication, RNA viruses must also maintain highly conserved genomic segments. A balance between conserved and variable viral elements is especially important in order for viruses to avoid ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/jvi.76.17.8505-8517.2002
更新日期:2002-09-01 00:00:00
abstract::The genome of the human immunodeficiency virus type 1 (HIV-1) is highly heterogeneous. Some of this genomic variability is reflected in the biologic and serologic differences observed among various strains of HIV-1. To map the viral determinants that correlate with pathogenicity of the virus, recombinant viruses were ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.64.9.4390-4398.1990
更新日期:1990-09-01 00:00:00
abstract::To improve the safety of recombinant vaccinia virus vaccines, modified vaccinia virus Ankara (MVA) has been employed, because it has a replication defect in most mammalian cells. Here we apply MVA to human immunodeficiency virus type 1 (HIV-1) vaccine development by incorporating the envelope protein gp160 of HIV-1 pr...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.72.10.8264-8272.1998
更新日期:1998-10-01 00:00:00
abstract::Replication of human papillomavirus type 11 (HPV-11) DNA requires the full-length viral E1 and E2 proteins (C.-M. Chiang, M. Ustav, A. Stenlund, T. F. Ho, T. R. Broker, and L. T. Chow, Proc. Natl. Acad. Sci. USA 89:5799-5803, 1992). Using transient transfection of subgenomic HPV DNA into hamster CHO and human 293 cell...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.66.9.5224-5231.1992
更新日期:1992-09-01 00:00:00
abstract::Proliferative cell nuclear antigen (PCNA), a conserved plant protein as well as an important replication factor, is induced in response to geminivirus infection in the resting cells of the phloem tissues. The biochemical role of PCNA in rolling circle replication (RCR) of geminivirus DNA has not been explored in detai...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.78.21.11890-11903.2004
更新日期:2004-11-01 00:00:00
abstract::The characteristics of fusion of respiratory syncytial virus (RSV) with HEp-2 cells were studied by the R18 fluorescence dequenching assay of membrane fusion. A gradual increase in fluorescence intensity indicative of virion-cell fusion was observed when R18-labeled RSV was incubated with HEp-2 cells. Approximately 35...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.65.8.4063-4069.1991
更新日期:1991-08-01 00:00:00
abstract::The hepatitis B virus (HBV) capsid or core protein (Cp) can self-assemble to form an icosahedral capsid. It is now being pursued as a target for small-molecule antivirals that enhance the rate and extent of its assembly to yield empty and/or aberrant capsids. These small molecules are thus called core protein alloster...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.01082-18
更新日期:2018-09-26 00:00:00
abstract::Porcine reproductive and respiratory syndrome virus (PRRSV) infection of swine leads to a serious disease characterized by a delayed and defective adaptive immune response. It is hypothesized that a suboptimal innate immune response is responsible for the disease pathogenesis. In the study presented here we tested thi...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.01326-09
更新日期:2010-02-01 00:00:00
abstract::Purified nuclei from polyoma-infected mouse (3T3) cells were found to be greatly reduced in their ability to synthesize viral DNA in vitro when compared with a crude system consisting of an unfractionated hypotonic lysate of the infected cells. The synthetic capacity of the nuclei could be fully reconstituted when a h...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.15.1.97-107.1975
更新日期:1975-01-01 00:00:00
abstract::Influenza viruses resistant to the neuraminidase (NA) inhibitor oseltamivir arise under drug selection pressure both in vitro and in vivo. Several mutations in the active site of the viral NA are known to confer relative resistance to oseltamivir, and influenza viruses with certain oseltamivir resistance mutations hav...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.01226-08
更新日期:2008-10-01 00:00:00
abstract::The catalytic core domain (CCD) of human immunodeficiency virus type 1 (HIV-1) integrase (IN) harbors the enzyme active site and binds viral and chromosomal DNA during integration. Thirty-five CCD mutant viruses were constructed, paying particular attention to conserved residues in the Phe(139)-Gln(146) flexible loop ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.79.4.2493-2505.2005
更新日期:2005-02-01 00:00:00
abstract::3-O-(3',3'-dimethylsuccinyl)betulinic acid (PA-457 or bevirimat) potently inhibits human immunodeficiency virus type 1 (HIV-1) maturation by blocking a late step in the Gag processing pathway, specifically the cleavage of SP1 from the C terminus of capsid (CA). To gain insights into the mechanism(s) by which HIV-1 cou...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.01369-06
更新日期:2006-11-01 00:00:00
abstract::We have shown previously that processing of the Sindbis virus envelope protein precursor PE2 to envelope protein E2 is not required for virus maturation in cultured vertebrate fibroblast cells and that unprocessed PE2 can be incorporated into infectious virus in place of E2 (J. F. Presley and D. T. Brown, J. Virol. 63...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.65.4.1905-1909.1991
更新日期:1991-04-01 00:00:00
abstract:UNLABELLED:During the chronic phase of HIV-1 infection, polyfunctional CD8+ T cell responses, which are characterized by a high frequency of cells able to secrete multiple cytokines simultaneously, are associated with lower virus loads and slower disease progression. This relationship may arise for different reasons. P...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.00647-14
更新日期:2014-09-01 00:00:00
abstract::Murine gammaherpesvirus 68 (gammaHV68, or MHV-68) is a genetically tractable, small animal model for the analysis of gammaherpesvirus pathogenesis. The gammaHV68 genome is colinear with the genomes of other sequence gammaherpesviruses, containing large blocks of conserved genes interspersed by a number of putative gen...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/jvi.74.4.1973-1984.2000
更新日期:2000-02-01 00:00:00
abstract::The genome of all densoviruses (DNVs) so far isolated from mosquitoes or mosquito cell lines consists of a 4-kb single-stranded DNA molecule with a monosense organization (genus Brevidensovirus, subfamily Densovirinae). We previously reported the isolation of a Culex pipiens DNV (CpDNV) that differs significantly from...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.00524-09
更新日期:2009-07-01 00:00:00
abstract::Three defense functions of immunoglobulin A (IgA), immune exclusion, intracellular neutralization, and virus excretion, were assessed in a measles virus model using polarized epithelial cells expressing the polymeric immunoglobulin receptor and monoclonal antibodies against the viral H and F envelope proteins and the ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/jvi.76.21.10972-10979.2002
更新日期:2002-11-01 00:00:00
abstract::Human cytomegalovirus (HCMV) major immediate-early protein IE1 is an abundant 72-kDa nuclear phosphoprotein that is thought to play an important role in efficient triggering of the lytic cycle, especially at low multiplicity of infection. The best-known properties of IE1 at present are its transient targeting to punct...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.75.22.10683-10695.2001
更新日期:2001-11-01 00:00:00
abstract::The DA strain and other members of the TO subgroup of Theiler's murine encephalomyelitis virus (TMEV) induce an early transient subclinical neuronal disease followed by a chronic progressive inflammatory demyelination, with persistence of the virus in the central nervous system (CNS) for the life of the mouse. Althoug...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.00178-11
更新日期:2011-09-01 00:00:00
abstract:UNLABELLED:Noroviruses are the leading cause of acute gastroenteritis outbreaks worldwide. The majority of norovirus outbreaks are caused by genogroup II.4 (GII.4). Novel GII.4 strains emerge every 2 to 4 years and replace older variants as the dominant norovirus. Novel variants emerge through a combination of recombin...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.02494-14
更新日期:2014-12-01 00:00:00
abstract::To understand the roles of heptad repeat 1(HR1) and HR2 of the spike (S) protein of the severe acute respiratory syndrome coronavirus (SARS-CoV) in virus-cell interactions, the conserved Leu or Ile residues located at positions 913, 927, 941, and 955 in HR1 and 1151, 1165, and 1179 in HR2 were individually replaced wi...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.80.7.3225-3237.2006
更新日期:2006-04-01 00:00:00