Abstract:
UNLABELLED:Broadly neutralizing antibodies (bNAbs) specific for conserved epitopes on the HIV-1 envelope (Env) are believed to be essential for protection against multiple HIV-1 clades. However, vaccines capable of stimulating the production of bNAbs remain a major challenge. Given that polyreactivity and autoreactivity are considered important characteristics of anti-HIV bNAbs, we designed an HIV vaccine incorporating the molecular adjuvants BAFF (B cell activating factor) and APRIL (a proliferation-inducing ligand) with the potential to facilitate the maturation of polyreactive and autoreactive B cells as well as to enhance the affinity and/or avidity of Env-specific antibodies. We designed recombinant DNA plasmids encoding soluble multitrimers of BAFF and APRIL using surfactant protein D as a scaffold, and we vaccinated mice with these molecular adjuvants using DNA and DNA-protein vaccination strategies. We found that immunization of mice with a DNA vaccine encoding BAFF or APRIL multitrimers, together with interleukin 12 (IL-12) and membrane-bound HIV-1 Env gp140, induced neutralizing antibodies against tier 1 and tier 2 (vaccine strain) viruses. The APRIL-containing vaccine was particularly effective at generating tier 2 neutralizing antibodies following a protein boost. These BAFF and APRIL effects coincided with an enhanced germinal center (GC) reaction, increased anti-gp120 antibody-secreting cells, and increased anti-gp120 functional avidity. Notably, BAFF and APRIL did not cause indiscriminate B cell expansion or an increase in total IgG. We propose that BAFF and APRIL multitrimers are promising molecular adjuvants for vaccines designed to induce bNAbs against HIV-1. IMPORTANCE:Recent identification of antibodies that neutralize most HIV-1 strains has revived hopes and efforts to create novel vaccines that can effectively stimulate HIV-1 neutralizing antibodies. However, the multiple immune evasion properties of HIV have hampered these efforts. These include the instability of the gp120 trimer, the inaccessibility of the conserved sequences, highly variable protein sequences, and the loss of HIV-1-specific antibody-producing cells during development. We have shown previously that tumor necrosis factor (TNF) superfamily ligands, including BAFF and APRIL, can be multitrimerized using the lung protein SP-D (surfactant protein D), enhancing immune responses. Here we show that DNA or DNA-protein vaccines encoding BAFF or APRIL multitrimers, IL-12p70, and membrane-bound HIV-1 Env gp140 induced tier 1 and tier 2 neutralizing antibodies in a mouse model. BAFF and APRIL enhanced the immune reaction, improved antibody binding, and increased the numbers of anti-HIV-1 antibody-secreting cells. Adaptation of this vaccine design may prove useful in designing preventive HIV-1 vaccines for humans.
journal_name
J Viroljournal_title
Journal of virologyauthors
Gupta S,Clark ES,Termini JM,Boucher J,Kanagavelu S,LeBranche CC,Abraham S,Montefiori DC,Khan WN,Stone GWdoi
10.1128/JVI.02904-14subject
Has Abstractpub_date
2015-04-01 00:00:00pages
4158-69issue
8eissn
0022-538Xissn
1098-5514pii
JVI.02904-14journal_volume
89pub_type
杂志文章abstract::The cellular protein bone marrow stromal antigen-2 (BST-2)/tetherin acts against a variety of enveloped viruses by restricting their release from the plasma membrane. The HIV-1 accessory protein Vpu counteracts BST-2 by downregulating it from the cell surface and displacing it from virion assembly sites. Previous comp...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.02315-18
更新日期:2019-05-15 00:00:00
abstract::Measles virus (MeV) infection is characterized by the formation of multinuclear giant cells (MGC). We report that beta interferon (IFN-beta) production is amplified in vitro by the formation of virus-induced MGC derived from human epithelial cells or mature conventional dendritic cells. Both fusion and IFN-beta respon...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.00078-07
更新日期:2007-12-01 00:00:00
abstract::Interaction between viral proteins is necessary for viral replication and viral particle assembly. We used the yeast two-hybrid assay to identify interactions among all the mature proteins of the hepatitis C virus. The interaction between NS3 and NS3 was one of the strongest viral protein-protein interactions detected...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.75.1.205-214.2001
更新日期:2001-01-01 00:00:00
abstract::Ebola virus (EBOV) causes a lethal hemorrhagic fever for which there is no approved effective treatment or prevention strategy. EBOV VP35 is a virulence factor that blocks innate antiviral host responses, including the induction of and response to alpha/beta interferon. VP35 is also an RNA silencing suppressor (RSS). ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.05741-11
更新日期:2012-03-01 00:00:00
abstract::We have investigated the antigenicity of the C- and N-terminal halves of pIX of human adenovirus types 2 and 3 (Ad2 and Ad3) as well as their orientations in virions. We found that only the C-terminal halves of Ad2 pIX and Ad3 pIX reacted in a subgenus-specific manner by enzyme-linked immunosorbent assay and immunoblo...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.73.7.6182-6187.1999
更新日期:1999-07-01 00:00:00
abstract::The DA strain of Theiler's murine encephalomyelitis virus persists in the white matter of the spinal cords of susceptible mice. Previous results showed that the difference in susceptibility to viral persistence between the susceptible SJL/J strain and the resistant B10.S strain was due to multiple non-H-2 loci. The re...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/jvi.76.11.5807-5812.2002
更新日期:2002-06-01 00:00:00
abstract::We used a transfected L cell and a vaccinia vector carrying the herpes simplex virus type 1 (HSV-1) gene coding for glycoprotein D (gD) to characterize HSV-specific T-cell responses. Various studies with mice revealed that the vectors could stimulate some HSV-specific T-cell responses. Although the majority of the T c...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.61.3.726-734.1987
更新日期:1987-03-01 00:00:00
abstract::Three of thirty-six monoclonal antibodies were found to cause irreversible inactivation of type 1 poliovirus at 39 degrees C but not at 37 degrees C. Neutralization at 37 degrees C depended on aggregation and was reversible by acid-induced deaggregation; at 39 degrees C, the virions (N antigenic, 160S) were disrupted ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.67.9.5299-5302.1993
更新日期:1993-09-01 00:00:00
abstract::Herpes B virus (BV) naturally infects macaque monkeys and is genetically similar to herpes simplex virus (HSV). Zoonotic infection of humans can cause encephalitis and if untreated has a fatality rate of ∼80%. The frequent use of macaques in biomedical research emphasizes the need to understand the molecular basis of ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.00505-11
更新日期:2011-07-01 00:00:00
abstract::Large numbers of polymorphonuclear leukocytes (PMNs) infiltrated the murine vaginal mucosa within 24 h after intravaginal inoculation with an attenuated strain of herpes simplex virus type 2 (HSV-2). The role of these cells in resolution of a primary genital infection and in protection of HSV-immune animals against ch...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.73.8.6380-6386.1999
更新日期:1999-08-01 00:00:00
abstract::Dengue virus (DENV) is a major global pathogen that causes significant morbidity and mortality in tropical and subtropical areas worldwide. An improved understanding of the regions within the DENV genome and its encoded proteins that are required for the virus replication cycle will expedite the development of urgentl...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.01455-17
更新日期:2017-11-14 00:00:00
abstract::We have identified nucleotide sequences that regulate transcription in both a cell-type-specific and general manner in the long terminal repeat of the MCF13 murine leukemia virus. Besides the enhancer element, we have observed that the region between the enhancer and promoter (DEN) has a profound effect on transcripti...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.66.12.7080-7088.1992
更新日期:1992-12-01 00:00:00
abstract::Various mechanisms are used by single-stranded RNA viruses to initiate and control their replication via the synthesis of replicative intermediates. In general, the same virus-encoded polymerase is responsible for both genome and antigenome strand synthesis from two different, although related promoters. Here we aimed...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.80.5.2337-2348.2006
更新日期:2006-03-01 00:00:00
abstract::Type III interferons ([IFNs] IFN-lambda and interleukin-28 and -29 [IL-28/29]) are recently recognized cytokines with innate antiviral effects similar to those of type I IFNs (IFN-alpha/beta). Like IFN-alpha/beta, IFN-lambda-expression can be induced by viruses, and it is believed that type I and III IFNs are regulate...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.00717-10
更新日期:2010-09-01 00:00:00
abstract::In addition to PTAP L domains, primate lentiviruses carry Alix-binding motifs that include the recently described type 3 SREKPYKEVTEDLLHLNSLF sequence. We examined the requirements for the type 3 sequence motif in simian immunodeficiency virus SIV(smE543) and identified the (499)LNSLF(503) sequence as a key functional...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.05284-11
更新日期:2011-11-01 00:00:00
abstract::Intragastric inoculation with whole-virion vaccine of inactivated influenza virus resulted in production of hemagglutinin (HA)-specific immunoglobulin A (IgA) and IgG both in lung lavage fluids and in serum samples of mice. HA-specific IgA was the predominant isotypic antibody secreted in the lung lavage fluids (avera...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.61.7.2150-2154.1987
更新日期:1987-07-01 00:00:00
abstract::Domains required late in the virus budding process (L domains) have been identified in the Gag proteins of a number of retroviruses. Here we show that the human T-cell leukemia virus type 1 candidate L domain motif PPPY is indeed required for virus production. Strikingly, however, mutation of this motif arrested virus...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/jvi.76.19.10024-10029.2002
更新日期:2002-10-01 00:00:00
abstract::An in vitro method which led to the transformation of hamster embryo fibroblasts after exposure to herpes simplex virus type 2 (HSV-2) inactivated with ultraviolet irradiation is described. The transformed cells (333-8-9) produced tumors when inoculated into newborn Syrian hamsters but not when injected into weanling ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.8.4.469-477.1971
更新日期:1971-10-01 00:00:00
abstract::Taking advantage of the wide tropism of baculoviruses (BVs), we constructed a recombinant BV (BV(CAR)) pseudotyped with human coxsackie B-adenovirus receptor (CAR), the high-affinity attachment receptor for adenovirus type 5 (Ad5), and used the strategy of piggybacking Ad5-green fluorescent protein (Ad5GFP) vector on ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.00012-09
更新日期:2009-06-01 00:00:00
abstract::Infection with the murine coronavirus strain JHM decreases cell surface expression of major histocompatibility complex class I antigens. Northern blots showed that JHM virus infection rapidly reduced the level of actin mRNA, whereas the levels of major histocompatibility complex class I and tubulin mRNAs were reduced ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.68.10.6815-6819.1994
更新日期:1994-10-01 00:00:00
abstract::Infection of cells with herpes simplex virus type 1 (HSV-1) results in a rapid alteration of phosphorylation on the large subunit of cellular RNA polymerase II (RNAP II), most likely on its C-terminal domain (S. A. Rice, M. C. Long, V. Lam, C. A. Spencer, J. Virol. 68:988-1001, 1994). This phosphorylation modification...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.69.9.5550-5559.1995
更新日期:1995-09-01 00:00:00
abstract::Noroviruses (NoVs) are a leading cause of gastroenteritis worldwide, yet host factors that restrict NoV replication are not well understood. Here, we use a CRISPR activation genome-wide screening to identify host genes that can inhibit murine norovirus (MNoV) replication in human cells. Our screens identified with hig...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.01324-18
更新日期:2018-12-10 00:00:00
abstract::Several early genes of murine cytomegalovirus (MCMV) encode proteins that mediate immune evasion by interference with the major histocompatibility complex class I (MHC-I) pathway of antigen presentation to cytolytic T lymphocytes (CTL). Specifically, the m152 gene product gp37/40 causes retention of MHC-I molecules in...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/jvi.74.4.1871-1884.2000
更新日期:2000-02-01 00:00:00
abstract::The presence of cycloheximide, an inhibitor of protein synthesis, during the period 30 to 60 min after vaccinia infection produced an irreversible block in virus replication. In contrast (i) cycloheximide given at earlier or later times, even for prolonged periods, did not prevent continuation of the infectious cycle ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.5.2.99-108.1970
更新日期:1970-02-01 00:00:00
abstract::The fundamental question of whether a primed immune system is capable of preventing latent gammaherpesvirus infection remains unanswered. Recent studies showing that vaccination can reduce acute replication and short-term latency but cannot alter long-term latency further call into question the possibility of achievin...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/jvi.77.4.2522-2529.2003
更新日期:2003-02-01 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::We have developed a simple screening method to identify genes that mimic bcl-2 or adenovirus E1B 19K in enhancing cell survival after transfection and have used this method to identify such a gene in the avian adenovirus CELO. The gene encodes a novel 30-kDa nuclear protein, which we have named GAM-1, that functions c...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.71.4.3168-3177.1997
更新日期:1997-04-01 00:00:00
abstract::Chronic hepatitis B affects over 300 million people who are at risk of developing liver cancer. The basis for the persistence of hepatitis B virus (HBV) in hepatocytes, even in the presence of available antiviral therapies, lies in the accumulation of covalently closed circular DNA (cccDNA) in nuclei of infected cells...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.01391-17
更新日期:2017-12-14 00:00:00
abstract::Borna disease virus (BDV) is a nonsegmented negative-strand (NNS) RNA virus that is unusual because it replicates in the nucleus. The most abundant viral protein in infected cells is a 38/39-kDa doublet that is presumed to represent the nucleocapsid. Infectious particles also contain high levels of this protein, accou...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.71.7.5133-5139.1997
更新日期:1997-07-01 00:00:00
abstract::During the 2009 H1N1 influenza virus pandemic (pdmH1N1) outbreak, it was found that most individuals lacked antibodies against the new pdmH1N1 virus, and only the elderly showed anti-hemagglutinin (anti-HA) antibodies that were cross-reactive with the new strains. Different studies have demonstrated that prior contact...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.05540-11
更新日期:2012-02-01 00:00:00