RESISTANCE OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 TO NEUTRALIZATION BY NATURAL ANTISERA OCCURS THROUGH SINGLE AMINO-ACID SUBSTITUTIONS THATCAUSE CHANGES IN ANTIBODY-BINDING AT MULTIPLE SITES

The ability of human immunodeficiency virus type 1 (HIV-1) to replicat e in the presence of strong immune responses to the virus may be due t o its high mutation rate, which provides envelope gene variability for selection of neutralization-resistant variants. Understanding neutral ization escape mechanisms is therefore important for the design of HIV -1 vaccines and our understanding of the disease process, In this repo rt, we analyze mutations at amino acid positions 281 and 582 in the HI V-1 envelope, where substitutions confer resistance to broadly reactiv e neutralizing antisera from seropositive individuals, Neither of thes e mutations lies within an antibody-binding site, and therefore the me chanism of immune escape in both cases is by alteration of the shape o f the envelope proteins. The conformation of the CD4-binding site is s hown to be critical with regard to presentation of other discontinuous epitopes. From our analysis of the neutralization of these variants, we conclude that escape from polyclonal sera occurs through alteration s at several different epitopes, generally resulting from single amino acid substitutions which influence envelope conformation. Experiments on a double mutant showed that the combination of both mutations is n ot additive, suggesting that these variants utilized alternate pathway s to elicit similar alterations of the HIV-1 envelope structure.