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Rega Institute for Medical Research, Katholieke Universiteit
Leuven, B-3000 Leuven, Belgium
Polyanionic compounds are known to inhibit the binding of human
immunodeficiency 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 cells in the presence of DS
Mr 5000. DS did not inhibit the binding of
DS-resistant virus to MT-4 cells or syncytium formation between MOLT
cells 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
molecule 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 molecule, (ii) the virus is able to overcome the
inhibitory effect of DS on viral infectivity, (iii) cross-resistance
developed against those polyanionic compounds that are structurally
related to DS, and (iv) the molecular determinants of HIV cell tropism,
syncytium-inducing ability, coreceptor (fusin/CC-CKR5) utilization, and
polyanion resistance seem to be located in the env
genome of HIV and specifically in the V3 loop domain.
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