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Acquired immunodeficiency syndrome (AIDS) is caused by the human immunodeficiency virus HIV-1, whose entry into target cells is mediated by the HIV-1 envelope glycoproteins gp120 and gp41. Entry of the virus depends on interaction between target cell receptors and the gp120 exterior glycoprotein. A new study investigates the crystal structure of the gp120 surface glycoprotein. It is hoped that greater understanding of HIV-1's ability to penetrate the humoral immune response will help in vaccine design.

Acquired immunodeficiency syndrome (AIDS) develops when a host's CD4 lymphocytes are destroyed by the human immunodeficiency viruses HIV-1 and HIV-2. Viral envelope glycoproteins gp120 and CD4 mediate the HIV's entry into host cells. A new study investigates the structure of gp120, which reveals some surprising features, including a cavity-laden CD4-gp120 interface and a natural mechanism for receptor-induced conformational changes.

A single equilibrium intermediate was discovered during both thermal and denaturant-induced unfolding of sCD4, which is an extracellular portion of CD4, a transmembrane glycoprotein expressed on T-lymphocytes. Among the four regions of sCD4 there are important interactions, but the interaction energies cannot be calculated.

HIV infection is initiated by the selective interaction between the cellular receptor CD4 and gp120, the external envelope glycoprotein of the virus. We used analytical ultracentrifugation, titration calorimetry, and surface plasmon resonance biosensor analysis to characterize the assembly state, thermodynamics, and kinetics of the CD4-gp120 interaction. The binding thermodynamics were of unexpected magnitude; changes in enthalpy, entropy, and heat capacity greatly exceeded those described for typical protein-protein interactions. These unusual thermodynamic properties were observed with both intact gp120 and a deglycosylated and truncated form of gp120 protein that lacked hypervariable loops V1, V2, and V3 and segments of its N and C termini. Together with previous crystallographic studies, the large changes in heat capacity and entropy reveal that extensive structural rearrangements occur within the core of gp120 upon CD4 binding. CD spectral studies and slow kinetics of binding support this conclusion. These results indicate considerable conformational flexibility within gp120, which may relate to viral mechanisms for triggering infection and disguising conserved receptor-binding sites from the immune system.