Abstract
BackgroundHuman immunodeficiency virus (HIV) enters target cells by a membrane fusion process that involves a series of sequential interactions between its envelope glycoproteins, the CD4 receptor and CXCR4/CCR5 coreceptors. CD4 molecules are expressed at the cell surface of lymphocytes and monocytes mainly as monomers, but basal levels of CD4 dimers are also present at the cell surface of these cells. Previous evidence indicates that the membrane distal and proximal extracellular domains of CD4, respectively D1 and D4, are involved in receptor dimerization.ResultsHere, we have used A201 cell lines expressing two CD4 mutants, CD4-E91K, E92K (D1 mutant) and CD4-Q344E (D4 mutant), harboring dimerization defects to analyze the role of CD4 dimerization in HIV-1 entry. Using entry assays based on β-lactamase-Vpr or luciferase reporter activities, as well as virus encoding envelope glycoproteins derived from primary or laboratory-adapted strains, we obtained evidence suggesting an association between disruption of CD4 dimerization and increased viral entry efficiency.ConclusionTaken together, our results suggest that monomeric forms of CD4 are preferentially used by HIV-1 to gain entry into target cells, thus implying that the dimer/monomer ratio at the cell surface of HIV-1 target cells may modulate the efficiency of HIV-1 entry.
Highlights
Human immunodeficiency virus (HIV) enters target cells by a membrane fusion process that involves a series of sequential interactions between its envelope glycoproteins, the CD4 receptor and CXCR4/CCR5 coreceptors
Characterization of CD4 dimerization mutants To examine the role of CD4 dimers in HIV-1 entry, we made use of two CD4 mutants, namely CD4-E91K, E92K and CD4-Q344E that harbored mutations in two distinct regions of the molecule involved in CD4 dimerization
It was shown that CD4 dimerization induced by the binding of HIV-1 virions leads to the nuclear translocation of AP-1 and NF-κB [10]
Summary
Human immunodeficiency virus (HIV) enters target cells by a membrane fusion process that involves a series of sequential interactions between its envelope glycoproteins, the CD4 receptor and CXCR4/CCR5 coreceptors. The first step of this fusion process involves the binding of gp120, the surface subunit of the viral envelope glycoprotein (Env), to its primary receptor, CD4. This interaction induces conformational changes in both proteins that lead to subsequent binding of gp120 to its coreceptor, CCR5 or CXCR4. Coreceptor binding is thought to trigger major structural rearrangements in the transmembrane glycoprotein gp subunit, including the formation of a triple-stranded coiled-coil that enables the hydrophobic fusion peptide at the N-terminus of gp to insert into the target cell membrane. The subsequent signaling cascade was found to induce the nuclear translocation of the AP-1 and NF-κB transcription factors, promoting T-cell activation [10]
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