Abstract:
:The human immunodeficiency virus type 1 (HIV-1) entry inhibitor eCD4-Ig is a fusion of CD4-Ig and a coreceptor-mimetic peptide. eCD4-Ig is markedly more potent than CD4-Ig, with neutralization efficiencies approaching those of HIV-1 broadly neutralizing antibodies (bNAbs). However, unlike bNAbs, eCD4-Ig neutralized all HIV-1, HIV-2, and simian immunodeficiency virus (SIV) isolates that it has been tested against, suggesting that it may be useful in clinical settings, where antibody escape is a concern. Here, we characterize three new eCD4-Ig variants, each with a different architecture and each utilizing D1.22, a stabilized form of CD4 domain 1. These variants were 10- to 20-fold more potent than our original eCD4-Ig variant, with a construct bearing four D1.22 domains (eD1.22-HL-Ig) exhibiting the greatest potency. However, this variant mediated less efficient antibody-dependent cell-mediated cytotoxicity (ADCC) activity than eCD4-Ig itself or several other eCD4-Ig variants, including the smallest variant (eD1.22-Ig). A variant with the same architecture as the original eCD4-Ig (eD1.22-D2-Ig) showed modestly higher thermal stability and best prevented the promotion of infection of CCR5-positive, CD4-negative cells. All three variants, and eCD4-Ig itself, mediated more efficient shedding of the HIV-1 envelope glycoprotein gp120 than did CD4-Ig. Finally, we show that only three D1.22 mutations contributed to the potency of eD1.22-D2-Ig and that introduction of these changes into eCD4-Ig resulted in a variant 9-fold more potent than eCD4-Ig and 2-fold more potent than eD1.22-D2-Ig. These studies will assist in developing eCD4-Ig variants with properties optimized for prophylaxis, therapy, and cure applications.IMPORTANCE HIV-1 bNAbs have properties different from those of antiretroviral compounds. Specifically, antibodies can enlist immune effector cells to eliminate infected cells, whereas antiretroviral compounds simply interfere with various steps in the viral life cycle. Unfortunately, HIV-1 is adept at evading antibody recognition, limiting the utility of antibodies as a treatment for HIV-1 infection or as part of an effort to eradicate latently infected cells. eCD4-Ig is an antibody-like entry inhibitor that closely mimics HIV-1's obligate receptors. eCD4-Ig appears to be qualitatively different from antibodies, since it neutralizes all HIV-1, HIV-2, and SIV isolates. Here, we characterize three new structurally distinct eCD4-Ig variants and show that each excels in a key property useful to prevent, treat, or cure an HIV-1 infection. For example, one variant neutralized HIV-1 most efficiently, while others best enlisted natural killer cells to eliminate infected cells. These observations will help generate eCD4-Ig variants optimized for different clinical applications.
journal_name
J Viroljournal_title
Journal of virologyauthors
Fetzer I,Gardner MR,Davis-Gardner ME,Prasad NR,Alfant B,Weber JA,Farzan Mdoi
10.1128/JVI.02011-17subject
Has Abstractpub_date
2018-05-29 00:00:00issue
12eissn
0022-538Xissn
1098-5514pii
JVI.02011-17journal_volume
92pub_type
杂志文章abstract::We constructed a matched set of plasmids to investigate the interactions of essential core sequences of the simian virus 40 replication origin with flanking regulatory sequences. Deletions of either T-antigen-binding region I or the 21-base-pair repeated promoter elements reduced replication to 50 to 70% of wild-type ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.57.1.138-144.1986
更新日期:1986-01-01 00:00:00
abstract::Previous studies have suggested that the U(L)17 gene of herpes simplex virus type 1 (HSV-1) is essential for virus replication. In this study, viral mutants incorporating either a lacZ expression cassette in place of 1,490 bp of the 2,109-bp U(L)17 open reading frame [HSV-1(deltaU(L)17)] or a DNA oligomer containing a...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.72.5.3779-3788.1998
更新日期:1998-05-01 00:00:00
abstract::Nonglucosylated and fragmented T4 DNA shows a gene-specific variation in transformation efficiency. ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.12.2.397-400.1973
更新日期:1973-08-01 00:00:00
abstract::Major neutralization antigenic sites have been previously mapped by us on VP1, the largest capsid protein of poliovirus type 1. Here we report the first identification of the primary sequence of a neutralization antigenic site on capsid protein VP2. Inspection of the amino acid sequence of VP2 led to the selection and...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.52.2.719-721.1984
更新日期:1984-11-01 00:00:00
abstract::Integrase of human immunodeficiency virus type 1 (HIVIN) consists of 288 amino acids, and its minimum DNA-binding domain (MDBD) (amino acids [aa] 220 to 270) is required for the integration reaction. We produced and characterized four murine monoclonal antibodies (MAbs) to the MDBD of HIVIN (strain LAI). Immunoblot an...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.73.5.4475-4480.1999
更新日期:1999-05-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.67.8.4722-4731.1993
更新日期:1993-08-01 00:00:00
abstract:UNLABELLED:Epstein-Barr virus (EBV) is a well-established B-cell-tropic virus associated with various lymphoproliferative diseases of both B-cell and non-B-cell origin. EBV is associated with a number of T-cell lymphomas; however, in vitro studies utilizing prototypical EBV type 1 (EBV-1) laboratory strains have genera...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.03001-14
更新日期:2015-02-01 00:00:00
abstract::The production and selection of infectious vaccinia virus recombinants expressing foreign genes was facilitated by the construction of plasmid vectors. These vectors contain all or part of the vaccinia virus thymidine kinase (TK) gene interrupted by multiple unique restriction endonuclease sites placed adjacent to the...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.49.3.857-864.1984
更新日期:1984-03-01 00:00:00
abstract::The Moloney murine leukemia virus (MuLV) is a highly leukemogenic virus. To map the leukemogenic potential of Moloney MuLV, we constructed chimeric viral DNA genomes in vitro between parental cloned infectious viral DNA from Moloney and amphotropic 4070-A MuLVs. Infectious chimeric MuLVs were recovered by microinjecti...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.52.2.448-456.1984
更新日期:1984-11-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.00986-19
更新日期:2019-11-13 00:00:00
abstract::Sindbis virus (SINV) is an alphavirus that causes infection of neurons and encephalomyelitis in adult immunocompetent mice. Recovery can occur without apparent neurological damage. To better define the factors facilitating noncytolytic clearance of SINV in different regions of the central nervous system (CNS) and the ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.01152-06
更新日期:2007-06-01 00:00:00
abstract::Genomic replication of the negative-strand RNA viruses is dependent upon protein synthesis. To examine the requirement for protein synthesis in replication, we developed an in vitro system that supports the genome replication of defective interfering particles of the negative-strand rhabdovirus vesicular stomatitis vi...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.49.2.303-309.1984
更新日期:1984-02-01 00:00:00
abstract::We established previously that the temperature-dependent host range mutant, td CE 3, of vesicular stomatitis virus (VSV) New Jersey possesses temperature-sensitive RNA transcriptase activity. In this paper, we describe dissociation and reconstitution experiments designed to determine which VSV polypeptide is affected ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.22.2.381-388.1977
更新日期:1977-05-01 00:00:00
abstract::The RNAs of replication-defective murine and primate type C transforming viruses were analyzed for the presence of nucleotide sequences homologous to the genomes of their respective helper type C viruses by using DNAs complementary (cDNA) to either the 5'-terminal (cDNA5') or total (cDNAtotal) nucleotide sequences of ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.26.3.570-576.1978
更新日期:1978-06-01 00:00:00
abstract::Two species of basic internal proteins were found in osmotic shock supernatant solutions of bacteriophages T4B, T4D, T2H, T2L, and T6. The major species of protein isolated had a molecular weight of approximately 21,000 daltons, whereas the minor protein molecular weight was near 9,500 daltons. The two protein species...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.6.4.445-454.1970
更新日期:1970-10-01 00:00:00
abstract::Investigation of the human antibody response to the 1957 pandemic H2N2 influenza A virus has been largely limited to serologic studies. We generated five influenza virus hemagglutinin (HA)-reactive human monoclonal antibodies (MAbs) by hybridoma technology from the peripheral blood of healthy donors who were born betw...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.07158-11
更新日期:2012-06-01 00:00:00
abstract::To investigate the process of human immunodeficiency virus type 1 (HIV-1) evolution in vivo, a total of 179 HIV-1 V3 sequences derived from cell-free plasma were determined from serial samples in three epidemiologically linked individuals (one infected blood donor and two transfusion recipients) over a maximum period ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.71.3.2555-2561.1997
更新日期:1997-03-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.78.19.10442-10448.2004
更新日期:2004-10-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.25.2.570-578.1978
更新日期:1978-02-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/jvi.78.6.3110-3122.2004
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/jvi.76.14.7322-7328.2002
更新日期:2002-07-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/jvi.76.21.11155-11158.2002
更新日期:2002-11-01 00:00:00
abstract::The antiviral effects of nitric oxide (NO) on Japanese encephalitis virus (JEV), a member of the family Flaviviridae, were investigated in this study. In vitro, inhibition of replication of JEV in gamma interferon-activated RAW 264.7 murine macrophages was correlated to cellular NO production. When cocultured with inf...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.71.7.5227-5235.1997
更新日期:1997-07-01 00:00:00
abstract::The ascomycete Botrytis porri causes clove rot and leaf blight of garlic worldwide. We report here the biological and molecular features of a novel bipartite double-stranded RNA (dsRNA) mycovirus named Botrytis porri RNA virus 1 (BpRV1) from the hypovirulent strain GarlicBc-72 of B. porri. The BpRV1 genome comprises t...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.00292-12
更新日期:2012-06-01 00:00:00
abstract::The immune response to viral glycoproteins is often directed against conformation- and/or glycosylation-dependent structures; synthetic peptides and bacterially expressed proteins are inadequate probes for the mapping of such epitopes. This report describes a retroviral vector system that presents such native epitopes...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.68.1.400-410.1994
更新日期:1994-01-01 00:00:00
abstract::RNA plant viruses use various translational regulatory mechanisms to control their gene expression. Translational enhancement of viral mRNAs that leads to higher levels of protein synthesis from specific genes may be essential for the virus to successfully compete for cellular translational machinery. The control elem...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/jvi.76.3.1144-1153.2002
更新日期:2002-02-01 00:00:00
abstract::Human herpesvirus 8 (HHV-8) viral interleukin-6 (vIL-6) is a cytokine that is poorly secreted and localized largely to the endoplasmic reticulum (ER). It has been implicated, along with other HHV-8 proinflammatory and/or angiogenic viral proteins, in HHV-8-associated Kaposi's sarcoma, primary effusion lymphoma (PEL), ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.00909-20
更新日期:2020-09-15 00:00:00
abstract::The unit-length genome of human herpesvirus 6 (HHV-6) consists of a single unique component (U) bounded by direct repeats DRL and DRR and forms head-to-tail concatemers during productive infection. cis-elements which mediate cleavage and packaging of progeny virions (a sequences) are found at the termini of all herpes...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.68.5.3007-3014.1994
更新日期:1994-05-01 00:00:00
abstract::The D4R gene of vaccinia virus encodes a functional uracil-DNA glycosylase that is essential for viral viability (D. T. Stuart, C. Upton, M. A. Higman, E. G. Niles, and G. McFadden, J. Virol. 67:2503-2513, 1993), and a D4R mutant, ts4149, confers a conditional lethal defect in viral DNA replication (A. K. Millns, M. S...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.70.11.7965-7973.1996
更新日期:1996-11-01 00:00:00
abstract::Phosphorylation of viral proteins plays important roles in the influenza A virus (IAV) life cycle. By using mass spectrometry, we identified tyrosine 132 (Y132) as a phosphorylation site of the matrix protein (M1) of the influenza virus A/WSN/1933(H1N1). Phosphorylation at this site is essential to the process of viru...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.03024-12
更新日期:2013-06-01 00:00:00