Abstract:
UNLABELLED:The RV144 vaccine trial implicated epitopes in the C1 region of gp120 (A32-like epitopes) as targets of potentially protective antibody-dependent cellular cytotoxicity (ADCC) responses. A32-like epitopes are highly immunogenic, as infected or vaccinated individuals frequently produce antibodies specific for these determinants. Antibody titers, as measured by enzyme-linked immunosorbent assay (ELISA) against these epitopes, however, do not consistently correlate with protection. Here, we report crystal structures of CD4-stabilized gp120 cores complexed with the Fab fragments of two nonneutralizing, A32-like monoclonal antibodies (MAbs), N5-i5 and 2.2c, that compete for antigen binding and have similar antigen-binding affinities yet exhibit a 75-fold difference in ADCC potency. We find that these MAbs recognize overlapping epitopes formed by mobile layers 1 and 2 of the gp120 inner domain, including the C1 and C2 regions, but bind gp120 at different angles via juxtaposed VH and VL contact surfaces. A comparison of structural and immunological data further showed that antibody orientation on bound antigen and the capacity to form multivalent antigen-antibody complexes on target cells were key determinants of ADCC potency, with the latter process having the greater impact. These studies provide atomic-level definition of A32-like epitopes implicated as targets of protective antibodies in RV144. Moreover, these studies establish that epitope structure and mode of antibody binding can dramatically affect the potency of Fc-mediated effector function against HIV-1. These results provide key insights for understanding, refining, and improving the outcome of HIV vaccine trials, in which relevant immune responses are facilitated by A32-like elicited responses. IMPORTANCE:HIV-1 Env is a primary target for antibodies elicited during infection. Although a small number of infected individuals elicit broadly neutralizing antibodies, the bulk of the humoral response consists of antibodies that do not neutralize or do so with limited breadth but may effect protection through Fc receptor-dependent processes, such as antibody-dependent cellular cytotoxicity (ADCC). Understanding these nonneutralizing responses is an important aspect of elucidating the complete spectrum of immune response against HIV-1 infection. With this report, we provide the first atomic-level definition of nonneutralizing CD4-induced epitopes in the N-terminal region of the HIV-1 gp120 (A32-like epitopes). Further, our studies point to the dominant role of precise epitope targeting and mode of antibody attachment in ADCC responses even when largely overlapping epitopes are involved. Such information provides key insights into the mechanisms of Fc-mediated function of antibodies to HIV-1 and will help us understand the outcome of vaccine trials based on humoral immunity.
journal_name
J Viroljournal_title
Journal of virologyauthors
Acharya P,Tolbert WD,Gohain N,Wu X,Yu L,Liu T,Huang W,Huang CC,Kwon YD,Louder RK,Luongo TS,McLellan JS,Pancera M,Yang Y,Zhang B,Flinko R,Foulke JS Jr,Sajadi MM,Kamin-Lewis R,Robinson JE,Martin L,Kwong PD,Guandoi
10.1128/JVI.02194-14subject
Has Abstractpub_date
2014-11-01 00:00:00pages
12895-906issue
21eissn
0022-538Xissn
1098-5514pii
JVI.02194-14journal_volume
88pub_type
杂志文章abstract::The effect of bacteriophage SPO1 infection of Bacillus subtilis and a deoxyribonucleic acid (DNA) polymerase-deficient (pol(-)) mutant of this microorganism on the synthesis of DNA has been examined. Soon after infection, the incorporation of deoxyribonucleoside triphosphates into acid-insoluble material by cell lysat...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.9.2.263-272.1972
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.61.12.3665-3671.1987
更新日期:1987-12-01 00:00:00
abstract::Defective interfering particles (DIPs) of equine herpesvirus 1 (EHV-1; Kentucky A strain) mediate persistent infection. DNA sequences at the L terminus, which contain the UL2 gene (homolog of UL55 of herpes simplex virus type 1 and open reading frame 3 of varicella-zoster virus) of standard EHV-1, have been shown to b...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.67.4.2255-2265.1993
更新日期:1993-04-01 00:00:00
abstract:UNLABELLED:Hepatitis C virus (HCV) infects 180 million people worldwide and is a leading cause of liver diseases such as fibrosis, cirrhosis, and hepatocellular carcinoma. It has been shown that HCV can spread to naive cells using two distinct entry mechanisms, "cell-free" entry of infectious extracellular virions that...
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abstract::The roles of the capsid protein (CP) and the CP coding sequence of tobacco etch potyvirus (TEV) in genome amplification were analyzed. A series of frameshift-stop codon mutations that interrupted translation of the CP coding sequence at various positions were introduced into the TEV genome. A series of 3' deletion mut...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.70.7.4370-4379.1996
更新日期:1996-07-01 00:00:00
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pub_type: 杂志文章
doi:10.1128/JVI.78.15.8382-8391.2004
更新日期:2004-08-01 00:00:00
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pub_type: 杂志文章
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更新日期:1994-10-01 00:00:00
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pub_type: 杂志文章,随机对照试验
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pub_type: 杂志文章
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更新日期:2009-07-01 00:00:00
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pub_type: 杂志文章
doi:10.1128/JVI.46.3.709-717.1983
更新日期:1983-06-01 00:00:00
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pub_type: 杂志文章
doi:10.1128/JVI.63.2.730-738.1989
更新日期:1989-02-01 00:00:00
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pub_type: 杂志文章
doi:10.1128/JVI.70.1.47-54.1996
更新日期:1996-01-01 00:00:00
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pub_type: 杂志文章
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更新日期:2007-12-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.33.1.522-530.1980
更新日期:1980-01-01 00:00:00
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pub_type: 杂志文章
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更新日期:2011-05-01 00:00:00
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pub_type: 杂志文章
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pub_type: 杂志文章
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更新日期:2012-04-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.02661-07
更新日期:2008-06-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.43.3.935-942.1982
更新日期:1982-09-01 00:00:00
abstract::Guinea pig antisera and mouse monoclonal antibodies against a 40,000-molecular-weight nucleocapsid protein (p40) of herpes simplex virus types 1 and 2 immunoprecipitated 40,000- and 80,000-molecular-weight classes of soluble proteins from infected cell extracts. The soluble 40,000-molecular-weight protein class (intra...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.35.3.644-652.1980
更新日期:1980-09-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
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更新日期:2010-04-01 00:00:00
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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
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.66.8.4705-4709.1992
更新日期:1992-08-01 00:00:00
abstract::Although in vitro replication of the hepatitis C virus (HCV) JFH1 clone of genotype 2a (HCVcc) has been developed, a robust cell culture system for the 1a and 1b genotypes, which are the most prevalent viruses in the world and resistant to interferon therapy, has not yet been established. As a surrogate virus system, ...
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更新日期:2007-08-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.70.11.8133-8137.1996
更新日期:1996-11-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.71.4.3357-3362.1997
更新日期:1997-04-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.64.6.3139-3143.1990
更新日期:1990-06-01 00:00:00
abstract:UNLABELLED:Ebola virus (EBOV) causes hemorrhagic fevers with high mortality rates. During cellular entry, the virus is internalized by macropinocytosis and trafficked through endosomes until fusion between the viral and an endosomal membrane is triggered, releasing the RNA genome into the cytoplasm. We found that while...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.03398-14
更新日期:2015-03-01 00:00:00