Characterization of the Specificity of the Human Antibody Response to the V3 Neutralization Domain of HIV-1

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Abstract
The major neutralization domain of HIV-1, contained in the third variable region (V3) of the external envelope, is highly variable at positions flanking a conserved glycine-proline-glycine sequence. We investigated the relation between V3 sequences of HIV-1 variants circulating in a host and that host's antibody specificity. Multiple V3 sequences were obtained directly, via PCR and subsequent cloning, from serum RNA or cellular DNA from 26 individuals (from 12 around seroconversion). Then, specificity of sera from these individuals to a panel of V3 peptides was determined. The specificity (best recognized peptide) of the early antibody response accurately reflected the virus population circulating around seroconversion in 12/12 individuals and 4/4 HIV-1-infected chimpanzees. A change in serum specificity at later stages of infection was rare: five years after seroconversion, only 3 of 46 individuals had a specificity that differed completely from that in the first year. However, the V3 domain of the virus does change over time, as evidenced by the poor correlation between V3 sequences obtained late in infection and V3 antibody reactivity at the same time point. Thus, in contrast to the accurate antibody response to HIV-1 variants early after infection, generally a specific response to variants emerging at later stages seemed to be absent or of low level. Instead, the early response appeared to be preserved. Finally, we made use of the observed accurate reflection to analyze the variation for the V3 domain of HIV-1 in the Netherlands by probing specificities of early sera from 129 Dutch seroconverting individuals. Specific reactivity to RKSIHIGPGRAFYTTG was found in 36%, to RKSINIGPGRAFYTTG in 12% and to RKSIPIGPGRAFYTTG in 18% of these Dutch sera.