Molecular Determinants of the V3 Loop of Human Immunodeficiency Virus Type 1 Glycoprotein gp120 Responsible for Controlling Cell Tropism

Department of Microbiology and Immunology, University of Leicester, Leicester LE1 9HN, U.K. We and others have identified the major determinant of cell tropism in human immunodeficiency virus type 1 (HIV-1) as the V3 loop of glycoprotein gp120. We have conducted a detailed study of two molecularly cloned isolates of HIV-1, HIV JR-CSF and HIV NL4-3 , that differ in their tropism for immortalized CD4 + cell lines, by constructing a series of site-directed mutations within the V3 loop of HIV JR-CSF based on the sequence of HIV NL4-3 . The phenotypes of these mutants fall into two classes, those which are viable and those which are not. A spontaneous mutant with significantly altered growth properties was also recovered and found to have an additional single amino acid change in the V3 loop sequence. The carboxy-terminal -strand part of the V3 loop is the major determinant 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 infected persons may be highly misleading. Present address: Sir William Dunn School of Pathology, South Parks Road, Oxford OX1 3RE, U.K. Received 27 April 1994; accepted 9 July 1994.