Molecular Mechanotransduction in Human CD4

HIV-1 infection initiates when the viral envelope glycoprotein gp120 interacts with two receptors on the surface of the T lymphocytes, CD4 and a chemokine co-receptor (CCR5 or CXCR4). Upon binding, a cascade of conformational changes in CD4 triggers viral fusion to the cell membrane. However, the key factors that originate the structural alterations in CD4 are unclear. Here, we use single-molecule force spectroscopy to study the mechanochemical properties of the two more external domains of human CD4 (D1 and D2). The application of mechanical forces to the CD4 domains reveals that they can be unfolded in a time-dependent manner within a biological range of forces. Similarly to other tandem repeats proteins such as titin or tenascin, mechanical unfolding of CD4 modules might be an important process occurring in vivo acting as a shock absorber. This phenomenon would help to prevent viral detachment. Furthermore, we show that mechanical exposition of internal disulfide bonds in CD4 is required for redox regulation by thioredoxin enzymes, a process that has been suggested to occur during viral infection. In addition, we perform numerical calculations using suitable models for polymer elasticity to correlate viral infectivity (Freeman et al. Structure 18(12):163241) with mechanical extensibility of CD4 modules. The role of mechanical forces in HIV-1 infection is yet to be considered, but it might represent a new view to better understand viral infection.