[85]). ADCC emerged as a correlate of reduced infection risk for vaccinees in the lower two-thirds of titre range for IgA antibodies specific for a C1 peptide,[86] raising the possibility that the IgA antibodies competitively inhibited ADCC by IgG in the upper third of the IgA responses. The ability of IgA mAbs isolated from RV144 vaccinees,[87] a 5-Fluoracil cell line specific highly conserved ADCC epitope recognized by the A32 mAb,[88] to block ADCC mediated by matched IgG1 mAbs specific for the same epitope was confirmed recently.[89] This suggests that vaccine-elicited antibodies to this epitope region contribute to decreased infection risk in RV144. This epitope
region is not a neutralization target,[26, 90] although it is a very potent ADCC target.[88, 90] As shown in Fig. 4(d), mutagenesis studies have
mapped the A32 epitope region to the C1 segment of gp120 involving mobile layers one and two,[91, 92] which we have confirmed and extended by mutagenesis and X-ray crystallography (in preparation). The importance of this region in protective immunity mediated by ADCC is supported by studies in natural infection and the RV144 trial. Importance of the A32 epitope region in natural infection is indicated by the ability of A32 Fab fragments to inhibit ADCC in most infected individuals.[88] It is also indicated by recognition of C1 peptides by polyclonal antibodies from infected individuals GPCR & G Protein inhibitor that mediate ADCC[88, 93] (Fig. 4(e,f) and isolation of A32-like mAbs that mediate potent ADCC from infected individuals.[90] Importantly, the A32 epitope region is also a target of ADCC-mediated viral escape early in infection[26] (Fig. 4f). With respect to acquisition, the A32 epitope region has been implicated as a target of antibodies that mediate ADCC, which correlate with reduced infection risk in RV144.[86, 89] The structural details of the A32 epitope region will be described in another report (in preparation) but the key
point for this discussion is its identification by four independent groups as a potent ADCC target in infected individuals[26, DCLK1 88, 90, 93] and that it appears to be a target of protective antibodies in the RV144 trial.[86, 87, 89] Collectively, these findings strongly point toward the importance of ADCC responses to the A32 epitope region in both blocking acquisition and in post-infection control of viraemia, raising the questions of where, when and how this happens. If these responses are important in blocking acquisition, they must occur before the establishment of the latent viral reservoir, which is likely to be in the first 3 days post-exposure when the small, infected founder population is established and expanded locally (Fig. 3).
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