Abstract
During natural HIV infection, an array of host receptors are thought to influence virus attachment and the kinetics of infection. In this study, to probe the interactions of HIV envelope (Env) with various receptors, we assessed the inhibitory properties of various anti-Env monoclonal antibodies (mAbs) in binding assays. To assist in detecting Env in attachment assays, we generated Fc fusions of full-length wild-type gp120 and several variable loop-deleted gp120s. Through investigation of the inhibition of Env binding to cell lines expressing CD4, CCR5, DC-SIGN, syndecans or combinations thereof, we found that the broadly neutralizing mAb, 2G12, directed to a unique carbohydrate epitope of gp120, inhibited Env-CCR5 binding, partially inhibited Env-DC-SIGN binding, but had no effect on Env-syndecan association. Furthermore, 2G12 inhibited Env attachment to primary monocyte-derived dendritic cells, that expressed CD4 and CCR5 primary HIV receptors, as well as DC-SIGN, and suggested that the dual activities of 2G12 could be valuable in vivo for inhibiting initial virus dissemination and propagation.
Highlights
The envelope glycoprotein (Env) of HIV mediates virus fusion and entry into susceptible cells [1]
The CD4i monoclonal antibodies (mAbs) 17b bound relatively weakly to the V3 loop-deleted gp120s, but soluble CD4 (sCD4) restored high affinity CD4i mAb binding to all constructs
Considering the higher affinity gp120-DCSIGN binding and that the competition analysis was consistent with our results in Fig. 5, we suggest that the ELISA format shown reflects the true gp120-dendritic cells (DCs)-SIGN binding relationship – partially inhibitable by 2G12, but not by V3 loop-specific mAbs
Summary
The envelope glycoprotein (Env) of HIV mediates virus fusion and entry into susceptible cells [1]. Env consists of a trimer of gp120/gp heterodimers, in which gp120 is the external surface subunit (SU) responsible for engaging cellular receptors and gp is the transmembrane subunit (TM) that mediates membrane fusion [1]. Infection occurs after sequential interactions of gp120 with cellular CD4 and a coreceptor, usually CCR5 or CXCR4. Because of its role in the infection process, Env is the principle target for neutralizing antibodies (nAbs). Very little progress has been made to date in developing vaccines able to elicit nAbs. The hope that one day these efforts may be fruitful is provided by the finding of a few (page number not for citation purposes)
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