MOLECULAR DETERMINANTS OF THE V3 LOOP OF HUMAN-IMMUNODEFICIENCY-VIRUSTYPE-1 GLYCOPROTEIN GP120 RESPONSIBLE FOR CONTROLLING CELL TROPISM

We and others have identified the major determinant of cell tropism in human immunodeficiency virus type 1 (HIV-1) as the V3 loop of glycopr otein gp120. We have conducted a detailed study of two molecularly clo ned isolates of HIV-1, HIVJR-CSF and HIVNL4-3, their tropism for immor talized CD4(+) cell lines, by constructing a series of site-directed m utations within the V3 loop of HIVJR-CSF based on the sequence of HIVN L4-3. The phenotypes of these mutants fall into two classes, those whi ch are viable and those which are not. A spontaneous mutant with signi ficantly altered growth properties was also recovered and found to hav e an additional single amino acid change in the V3 loop sequence. The carboxy-terminal beta-strand part of the V3 loop is the major determin ant of cell tropism. However, the results presented here indicate that the functional role of the V3 loop sequences can only be interpreted properly in the context of the original gp120 backbone from which they were derived. These findings show that over-simplistic interpretation of sequence data derived from unknown mixtures of HIV variants in inf ected persons may be highly misleading.