Abstract
The HIV-1 envelope glycoprotein (Env) mediates viral entry via conformational changes associated with binding the cell surface receptor (CD4) and coreceptor (CCR5/CXCR4), resulting in subsequent fusion of the viral and cellular membranes. While the gp120 Env surface subunit has been extensively studied for its role in viral entry and evasion of the host immune response, the gp41 transmembrane glycoprotein and its role in natural infection are less well characterized. Here, we identified a primary HIV-1 Env variant that consistently supports >300% increased viral infectivity in the presence of autologous or heterologous HIV-positive plasma. However, in the absence of HIV-positive plasma, viruses with this Env exhibited reduced infectivity that was not due to decreased CD4 binding. Using Env chimeras and sequence analysis, we mapped this phenotype to a change Q563R, in the gp41 heptad repeat 1 (HR1) region. We demonstrate that Q563R reduces viral infection by disrupting formation of the gp41 six-helix bundle required for virus-cell membrane fusion. Intriguingly, antibodies that bind cluster I epitopes on gp41 overcome this inhibitory effect, restoring infectivity to wild-type levels. We further demonstrate that the Q563R change increases HIV-1 sensitivity to broadly neutralizing antibodies (bNAbs) targeting the gp41 membrane-proximal external region (MPER). In summary, we identify an HIV-1 Env variant with impaired infectivity whose Env functionality is restored through the binding of host antibodies. These data contribute to our understanding of gp41 residues involved in membrane fusion and identify a mechanism by which host factors can alleviate a viral defect.
Highlights
HIV-1 envelope glycoprotein (Env) consists of two subunits: the surface-exposed glycoprotein gp120, which contains the receptor (CD4) and coreceptor (CCR5 or CXCR4) binding sites, and the transmembrane subunit gp41, which is critical for virus-cell membrane fusion [1,2,3,4,5]
We have identified a change in gp41, Q563R, that disrupts this six-helix bundle formation, negatively affecting viral entry and infection
We demonstrate that the Q563R change confers increased sensitivity to broadly neutralizing antibodies targeting the gp41 membrane-proximal external region (MPER)
Summary
HIV-1 Env consists of two subunits: the surface-exposed glycoprotein gp120, which contains the receptor (CD4) and coreceptor (CCR5 or CXCR4) binding sites, and the transmembrane subunit gp, which is critical for virus-cell membrane fusion [1,2,3,4,5]. Sequential binding of HIV-1 to its receptor and coreceptor are the first steps critical for viral entry [1, 8,9,10,11], whereby CD4 binding triggers a series of conformational changes in Env involving both gp120 and gp. Upon receptor and coreceptor binding, the fusion peptide in gp is inserted into the cell membrane and the HR1 and HR2 regions rearrange to form the six-helix bundle, which is critical for creation of the fusion pore to enable membrane fusion and efficient viral entry [13,14,15]
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