The HIV gp41 pocket binding domain enables C-terminal heptad repeat transition from mediating membrane fusion to immune modulation

For successful infection and propagation viruses must overcome many obstacles such as the immune system and entry into their host cells. The human immunodeficiency virus (HIV), utilizes its trimeric envelope protein gp160, specifically the gp41subunit, to enter its host cell. During this process, a gp41-central coiled-coilis formed from three N and three C terminal heptad repeats, termed the six helix bundle, which drives membrane fusion. Recently, T-cell suppression has been reported as an additional functionfor several regions of gp41by interfering with the T-cell receptorsignaling cascade. One of these regions encompasses the conserved pocket binding domainthat is situated in the C terminal heptad repeatand stabilizes six- helix bundleformation. This could indicate that the pocket binding domainplays a role in T-cell suppression in addition to its role in membrane fusion. To investigate this dual function, we used two independent cell cultures coupled with biophysical techniques. The data reveal that the pocket binding domainmediates T-cell suppression by stabilizing a T-cell receptorbinding conformation in the membrane. Moreover, we show that the clinically used HIV fusion inhibitorT-20 did not show suppressive abilities, in contrast to the potent fusion inhibitorC34. In addition, by focusing on six helix bundleconformation post its assembly, we shed light on a mechanism by which gp41’s function alternates from membrane fusion facilitation to suppression of T-cell receptoractivation.