Abstract
BackgroundThe structure of HIV-1 envelope glycoprotein (Env) is flexible and heterogeneous on whole virions. Although functional Env complexes are thought to require trimerization of cleaved gp41/gp120 heterodimers, variable processing can result in the potential incorporation of non-functional uncleaved proteins (gp160), non-trimeric arrangements of gp41/gp120 heterodimers, and gp120 depleted gp41 stumps. The potential distribution of functional and non-functional Env forms across replication-competent viral populations may have important implications for neutralizing and non-neutralizing antibody functions. This study applied an immuno-bead viral capture assay (VCA) to interrogate the potential distribution (heterologous vs homologous) of functional and non-functional forms of virion associated Env.ResultsThe VCA revealed a significant association between depletion of infectious virions and virion Env incorporation, but not between infectivity and p24-gag. Three distinct subpopulations of virions were identified within pools of genetically homogenous viral particles. Critically, a significant subpopulation of infectious virions were exclusively captured by neutralizing antibodies (nAbs) indicative of a homologous distribution of functional trimeric Env forms. A second infectious subpopulation bound both neutralizing and non-neutralizing antibodies (nnAbs) representative of a heterologous distribution of Env forms, while a third non-infectious subpopulation was predominantly bound by nnAbs recognizing gp41 stumps.ConclusionsThe observation that a distinct and significant subpopulation of infectious virions is exclusively captured by neutralizing antibodies has important implications for understanding antibody binding and neutralization, as well as other antibody effector functions.Electronic supplementary materialThe online version of this article (doi:10.1186/s12977-015-0207-z) contains supplementary material, which is available to authorized users.
Highlights
The structure of HIV-1 envelope glycoprotein (Env) is flexible and heterogeneous on whole virions
Successful vaccination to prevent HIV-1 acquisition will likely require the elicitation of neutralizing antibodies directed against the functional envelope glycoprotein (Env) [1,2,3]
Env‐specific monoclonal antibody (mAb) capture varying levels of total viral particles and gp120 positive virions An immuno-bead viral capture assay (VCA) was used to interrogate variability in the structure and conformation of Env glycoprotein incorporated into intact virions
Summary
The structure of HIV-1 envelope glycoprotein (Env) is flexible and heterogeneous on whole virions. The potential distribution of functional and non-functional Env forms across replication-competent viral populations may have important implications for neutralizing and non-neutralizing antibody functions. This study applied an immuno-bead viral capture assay (VCA) to interrogate the potential distribution (heterologous vs homologous) of functional and non-functional forms of virion associated Env. Successful vaccination to prevent HIV-1 acquisition will likely require the elicitation of neutralizing antibodies (nAb) directed against the functional envelope glycoprotein (Env) [1,2,3]. Virion Env diversity is generated by multiple mechanisms including: the range of virion incorporated Env structures, the degree and extent of Env glycosylation, the flexible nature of the HIV-1 Env protein, and potential instability on the surface of viral particles [8,9,10]. Subsequent proteolytic cleavage of gp160 by cellular furins into non-covalently attached transmembrane gp and external gp120 components is a necessary step in the creation of functional
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