Neutralization of the human immunodeficiency virus type 1 primary isolate JR-FL by human monoclonal antibodies correlates with antibody binding to the oligomeric form of the envelope glycoprotein complex

Fouts, Timothy; Binley, James Μ.; Trkola, Alexandra; Robinson, J.; Moore, John P.

doi:10.1128/jvi.71.4.2779-2785.1997

Cited by 216 publications

(57 citation statements)

References 74 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A more complete study of epitope exposure in dimeric and monomeric gp120 is being performed and will be reported elsewhere. It is well established that MAb binding to cell surface-expressed gp120 is more predictive of neutralization than is binding to purified soluble gp120 (12,28,33,34,43). It therefore seems likely that the quaternary structure of gp120 contributes to resistance to neutralization by limiting the exposure of potentially neutralizing epitopes.…”

Section: Discussionmentioning

confidence: 99%

“…The V3 domain appears to be well exposed in cell surface-expressed gp120 derived from T-cell-line-adapted strains but less well exposed in gp120 derived from a macrophage-tropic strain (24,34,39). Importantly, exposure of cell surface-expressed gp120 epitopes more accurately predicts the neutralizing activity of monoclonal antibodies (MAb) than the epitope exposure of purified soluble gp120 (12,28,33,34,43), although MAb binding may not always be sufficient for neutralization (13,40).…”

mentioning

confidence: 99%

See 1 more Smart Citation

The Human Immunodeficiency Virus Type 1 gp120 V2 Domain Mediates gp41-Independent Intersubunit Contacts

et al. 2000

View full text Add to dashboard Cite

The envelope protein of human immunodeficiency virus type 1 HIV-1 undergoes proteolytic cleavage in the Golgi complex to produce subunits designated gp120 and gp41, which remain noncovalently associated. While gp41 has a well-characterized oligomeric structure, the maintenance of gp41-independent gp120 intersubunit contacts remains a contentious issue. Using recombinant vaccinia virus to achieve high-level expression of gp120 in mammalian cells combined with gel filtration analysis, we were able to isolate a discrete oligomeric form of gp120. Oligomerization of gp120 occurred intracellularly between 30 and 120 min after synthesis. Analysis by sedimentation equilibrium unequivocally identified the oligomeric species as a dimer. In order to identify the domains involved in the intersubunit contact, we expressed a series of gp120 proteins lacking various domains and assessed the effects of mutation on oligomeric structure. Deletion of the V1 or V3 loops had little effect on the relative amounts of monomer and dimer in comparison to wild-type gp120. In contrast, deletion of either all or part of the V2 loop drastically reduced dimer formation, indicating that this domain is required for intersubunit contact formation. Consistent with this, the V2 loop of the dimer was less accessible than that of the monomer to a specific monoclonal antibody. Previous studies have shown that while the V2 loop is not an absolute requirement for viral entry, the absence of this domain reduces viral resistance to neutralization by monoclonal antibodies or sera. We propose that the quaternary structure of gp120 may contribute to resistance to neutralization by limiting the exposure of conserved epitopes.The envelope (env) proteins of human immunodeficiency virus type 1 (HIV-1) mediate viral entry and are the primary targets of neutralizing antibodies. Following synthesis and posttranslational modifications in the endoplasmic reticulum, including N-linked glycosylation, disulfide bond formation, and oligomerization, the env protein precursor gp160 passes through the Golgi complex where it is cleaved to form subunits designated gp120 and gp41 (11,41). A noncovalently associated oligomeric gp120-gp41 complex is transported to the surface of infected cells, where incorporation into budding virions occurs. The binding of virion-associated or infected-cell-associated gp120 to the CD4 receptor induces conformational changes that promote subsequent interaction with one of a number of chemokine receptors (19,46,49). Movement of the variable (V) loop structure V1/V2 following CD4 binding has been shown to result in increased exposure of an antibody epitope which overlaps with the chemokine receptor binding site (44,52). Receptor binding-induced env conformational changes are believed to culminate in the exposure of the gp41 fusion peptide and its repositioning toward the target cell prior to fusion of the membranes of the infected cell or virion and the target cell (5,14,26,48).Despite numerous investigations, the oligomeric structure of the nativ...

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

The Human Immunodeficiency Virus Type 1 gp120 V2 Domain Mediates gp41-Independent Intersubunit Contacts

et al. 2000

View full text Add to dashboard Cite

show abstract

“…Notably, this spatial organization allows the virus to occlude antigenic sites that are exposed on monomeric subunits. Only antibodies that react with the intact trimer are considered to bear neutralizing activity [51, 52]. However, these responses are minute compared with reactivities to the monomers which are likely presented in greater abundance to the immune system.…”

Section: Neutralizing Antibodies In Hiv Infectionmentioning

confidence: 99%

Humoral immunity to HIV‐1: neutralization and beyond

Huber

Trkola

2007

Journal of Internal Medicine

View full text Add to dashboard Cite

Humoral immunity is considered a key component of effective vaccines against HIV-1. Hence, an enormous effort has been put into investigating the neutralizing antibody response to HIV-1 over the past 20 years which generated key information on epitope specificity, potency, breadth and in vivo activity of the neutralizing antibodies. Less clear is still the role of antibody-mediated effector functions (antibodydependent cellular cytotoxicity, phagocytosis, complement system) and uncertainty prevails whether Fc-mediated mechanisms are largely beneficial or detrimental for the host. The current knowledge on the manifold functions of the humoral immune response in HIV infection, their underlying mechanisms and potential in vaccine-induced immunity will be discussed in this review.

show abstract

“…It has been proposed that conformationally dependent trimer-specific binding of Abs is a critical component of viral neutralization [7,19]. Conformational epitope specific Abs have been raised in mice by oligomeric vaccination [20], however these studies were performed with oligomeric forms of uncleaved gp140 constructs that exhibited heterogeneity in protein form.…”

Section: Critical Nature Of the Antigenmentioning

confidence: 99%

Emerging studies of human HIV-specific antibody repertoires

Hicar

Kalams

Spearman

et al. 2010

Vaccine

View full text Add to dashboard Cite

There has been an explosion of interest in the human B cell response to HIV infection of late. Recent advances in techniques for isolation of human antibodies and antibody secreting cell lines have facilitated a rapid expansion in the number of antibodies available for study. Early analysis of these repertoires reveals interesting features of the HIV-specific antibody response. HIV-specific repertoires exhibit a high level of clonality in circulating cells, and high levels of somatic mutations within the antibody variable gene segments. It appears that many if not most antibodies in circulation bind to virus envelope conformations that are found only in complex oligomeric structures on virion particles or virus-like particles. The rapid isolation of large panels of novel human neutralizing antibodies promises to reveal new insights into the fundamental principles underlying antibodymediated neutralization of HIV.

show abstract

Neutralization of the human immunodeficiency virus type 1 primary isolate JR-FL by human monoclonal antibodies correlates with antibody binding to the oligomeric form of the envelope glycoprotein complex

Cited by 216 publications

References 74 publications

The Human Immunodeficiency Virus Type 1 gp120 V2 Domain Mediates gp41-Independent Intersubunit Contacts

The Human Immunodeficiency Virus Type 1 gp120 V2 Domain Mediates gp41-Independent Intersubunit Contacts

Humoral immunity to HIV‐1: neutralization and beyond

Emerging studies of human HIV-specific antibody repertoires

Contact Info

Product

Resources

About