DEVELOPMENT OF RESISTANCE OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 TO DEXTRAN SULFATE ASSOCIATED WITH THE EMERGENCE OF SPECIFIC MUTATIONS IN THE ENVELOPE GP120 GLYCOPROTEIN

Polyanionic compounds are known to inhibit the binding of human immuno deficiency virus (HIV) to CD4(+) cells and the subsequent fusion step between the virus and cells. We selected an HIV-1 strain resistant to dextran sulfate (DS) by cultivation of HIV-1 (NL4-3)-infected MT-4 cel ls in the presence of DS M-r 5000. DS did not inhibit the binding of D S-resistant virus to MT-4 cells or syncytium formation between MOLT ce lls and HUT-78 cells persistently infected with the DS-resistant virus . In addition, a monoclonal antibody with specificity for the V3 loop of envelope gp120 glycoprotein did not recognize the DS-resistant HIV- 1 gp120 V3 loop. The following mutations were found in the gp120 molec ule of the DS-resistant HIV-1 strain but not in the wild-type strain: S114N in the V1 loop region; S134N in the V2 loop region; K269E, Q278H , and N293D in the V3 loop region; N323S in the C3 region; a deletion of five amino acids (Phe-Asn-Ser-Thr-Trp) at positions 364-368 in the V4 loop; and R387I in the CD4 binding domain. Our results suggest that (i) DS interacts with specific amino acid residues in the gp120 molec ule, (ii) the virus is able to overcome the inhibitory effect of DS on viral infectivity, (iii) cross-resistance developed against those pol yanionic compounds that are structurally related to DS, and (iv) the m olecular determinants of HIV cell tropism, syncytium-inducing ability, coreceptor (fusin/ CC-CKR5) utilization, and polyanion resistance see m to be located in the env genome of HIV and specifically in the V3 lo op domain.