PATTERNS OF AMINO-ACID VARIABILITY IN NSI-LIKE AND SI-LIKE V3 SEQUENCES AND A LINKED CHANGE IN THE CD4-BINDING DOMAIN OF THE HIV-I ENV PROTEIN

The V3 domain plays a central role in the biology of the HIV-I Env gly coprotein gp120 as a dominant target for neutralizing antibodies for s ome HIV-1 isolates, and as a major determinant in the switch from the nonsyncytium-inducing (RIS) to the syncytium-inducing (SI) form of HIV -1 that is associated with accelerated disease progression. Basic amin o acid substitutions are known to play an important role in the S1 phe notype. We have used the presence of basic amino acid substitutions in V3 sequences to divide sequences in a large data base into Si-like an d NSI-like. We found significant differences in features of sequence v ariability between these two groups of sequences. Of the thirty-six mo st frequent substitutions in V3, twenty appear disproportionately amon g either the Si like sequences or the NSI-like sequences. The fourteen favored substitutions among the SI-like sequences account for 50% oi the twofold increased variability seen in this group. In addition, we found a linked change within the CD4-binding domain of gp120 downstrea m of V3. These differences are interpreted in the context of structure , function, and selective pressure. An understanding of these patterns of sequence variability offers the possibility of designing a degener ate SI-specific V3 immunogen Po use as a therapeutic vaccine with the hope of slowing or preventing the appearance of SI variants, (C) 1997 Academic Press.