Abstract
The α4ß7 integrin present on host cells recognizes the V1V2 domain of the HIV-1 envelope protein. This interaction might be involved in virus transmission. Administration of α4ß7-specific antibodies inhibit acquisition of SIV in a macaque challenge model. But the molecular details of V1V2: α4ß7 interaction are unknown and its importance in HIV-1 infection remains controversial. Our biochemical and mutational analyses show that glycosylation is a key modulator of V1V2 conformation and binding to α4ß7. Partially glycosylated, but not fully glycosylated, envelope proteins are preferred substrates for α4ß7 binding. Surprisingly, monomers of the envelope protein bound strongly to α4ß7 whereas trimers bound poorly. Our results suggest that a conformationally flexible V1V2 domain allows binding of the HIV-1 virion to the α4ß7 integrin, which might impart selectivity for the poorly glycosylated HIV-1 envelope containing monomers to be more efficiently captured by α4ß7 integrin present on mucosal cells at the time of HIV-1 transmission.