The role of CD4 in HIV binding and entry

Area of Science:

• Virology
• Immunology
• Cell Biology

Background:

• The CD4 antigen is the primary cellular receptor for human and simian immunodeficiency viruses (HIV-1, HIV-2, SIV).
• HIV infection initiates via high-affinity binding between CD4's first domain and the viral envelope glycoprotein gp120.

Purpose of the Study:

• To analyze receptor binding and post-binding events leading to virus-cell membrane fusion using soluble recombinant CD4 (sCD4) as a mimic.
• To investigate the conformational changes in gp120 and gp41 induced by CD4 binding in HIV-1, HIV-2, and SIV.

Main Methods:

• Utilized soluble recombinant CD4 (sCD4) as a receptor mimic to study HIV-1, HIV-2, and SIV interactions.
• Observed conformational changes in gp120 and exposure of gp41 epitopes upon sCD4 binding to cell-line adapted HIV-1 isolates.
• Examined CD4 recruitment-induced gp41 epitope exposure at the fusion interface between CD4-expressing and HIV-infected cells.

Main Results:

• sCD4 binding to HIV-1 induces gp120 dissociation from gp41, exposing cryptic gp41 epitopes.
• Cell-anchored CD4 also leads to exposure of fusogenic gp41 epitopes at the virus-cell interface.
• CD4 binding induces more subtle molecular rearrangements in gp120 for HIV-2 and SIV compared to HIV-1.

Conclusions:

• CD4 binding triggers the exposure of fusogenic gp41 components, mediating virus-cell membrane fusion (receptor-mediated activation of fusion).
• A spectrum of responses to sCD4 binding exists across different lentiviruses, with HIV-1 showing more pronounced changes than HIV-2 and SIV.