EVIDENCE THAT THE STRUCTURAL CONFORMATION OF ENVELOPE GP120 AFFECTS HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 INFECTIVITY, HOST-RANGE, AND SYNCYTIUM-FORMING ABILITY

We investigated how amino acid changes within and outside the V3 loop of the envelope glycoprotein of human immunodeficiency virus type 1 in fluence the infectivity, host range, and syncytium-forming ability of the virus. Our studies show that on the genomic backgrounds of the hum an immunodeficiency virus type 1 strains SF2 and SF13, a reciprocal ex change of full-loop sequences does not alter the syncytium-forming abi lity of the viruses, indicating that a determinant(s) for this biologi cal property maps outside the loop. However, specific amino acid subst itutions, both within and outside the V3 loop, resulted in loss of inf ectivity, host range, and syncytium-forming potential of the virus. Fu rthermore, it appears that a functional interaction of the V3 loop wit h regions in the C2 domain of envelope gp120 plays a role in determini ng these biological properties. Structural studies of mutant glycoprot eins show that the mutations introduced affect the proper association of gp120 with the transmembrane glycoprotein gp41. Our results suggest that mutations that alter the structure of the V3 loop can affect the overall conformation of gp120 and that, reciprocally, the structure o f the V3 loop is influenced by the conformation of other regions of gp 120. Since the changes in the replicative potential, host range, and f usogenic ability of the mutant viruses correlate well with the changes in gp120 conformation, as monitored by the association of gp120 with gp41, our results support a close relationship between envelope gp120 structural conformation and the biological phenotype of the virus.