V3 LOOP OF THE HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 ENV PROTEIN - INTERPRETING SEQUENCE VARIABILITY

Two different states of human immunodeficiency virus type 1 are appare nt in the asymptomatic and late stages of infection. Important determi nants associated with these two states have been found within the V3 l oop of the viral Env protein. In this study, two large data sets of pu blished V3 sequences were analyzed to identify patterns of sequence va riability that would correspond to these two states of the virus. We w ere especially interested in the pattern of basic amino acid substitut ions, since the presence of basic amino acids in V3 has been shown to change virus tropism in cell culture. Four features of the sequence he terogeneity in V3 were observed: (i) approximately 70% of all nonconse rvative basic substitutions occur at four positions in V3, and V3 sequ ences with a basic substitution in at least one of these four position s contain approximately 95% of all nonconservative basic substitutions ; (ii) substitution patterns within V3 are influenced by the identity of the amino acid at position 25; (iii) sequence polymorphisms account for a significant fraction of uncharged amino acid substitutions at s everal positions in V3, and sequence heterogeneity other than these po lymorphisms is most significant at two positions near the tip of V3; a nd (iv) sequence heterogeneity in V3 (in addition to the basic amino a cid substitutions) is approximately twofold greater in V3 sequences th at contain basic amino acid substitutions. By using this sequence anal ysis, we were able to identify distinct groups of V3 sequences in infe cted patients that appear to correspond to these two virus states. The identification of these discrete sequence patterns in vivo demonstrat es how the V3 sequence can be used as a genetic marker for studying th e two states of human immunodeficiency virus type 1.