Antigenic significance of HIV-1 genetic variability

One of the key questions on HIV vaccine development is related to the immunological significance of the observed HIV genetic variability. Do different HIV-1 subtypes represent different immunological subtypes (or immunotypes)? If this is the case, what would be the relevance of these immunotypes for vaccine-induced protection?

One way to approach this problem is by studying the ability of different polyclonal and monoclonal antibodies to bind to viral proteins derived from different HIV-1 subtypes. The genetic variability of the V3 loop regions from different HIV-1 subtypes is reflected in their ability to bind specific antibodies in peptide-ELISA and, as discussed before, this has been exploited for subtyping purposes [32-34]. If neutralizing antibodies directed against the V3 loop sequences are important for protection, then this would impose the need to develop candidate vaccines containing cocktails of multiple V3 sequences representing the observed inter-clade, as well as intra-clade variability in this region.

Strain-specific neutralizing antibodies are generally directed against linear epitopes present in the V3 loop. However, more broadly reactive neutralizing antibodies can be elicited either to other linear epitopes (eg. in gp41) or to conformational epitopes related to the gp120/CD4-binding site [4,5]. It is interesting that monoclonal antibodies against conformational epitopes of subtype B gp120 molecules, were also capable of binding to gp120 molecules from strains belonging to clades A through F, although clade E strains were the least related to clade B viruses [35,36]. Moreover, monoclonal antibodies are also capable of cross-neutralizing primary isolates belonging to different genetic subtypes [37].

Preliminary checkerboard neutralization assays of HIV-1 primary isolates from different genetic subtypes, using autologous and heterologous plasma, failed to show any defined pattern of genetic subtype-specific neutralization. Most antisera either failed to neutralize primary isolates, or were broadly cross-neutralizing. These studies suggest that genetic subtypes of HIV-1 do not represent classical neutralization serotypes. On the other hand, these findings cannot exclude the possible existence of HIV neutralization serotypes, although they may not correspond to the known genetic subtypes [38,39]. Moreover, cross-neutralization between group M and group O viruses has also been described [40].

These results are very encouraging, because they indicate extensive antigenic conservation among HIV-1 strains from different subtypes. If neutralizing antibodies are important for vaccine-induced protection, then a broadly effective vaccine may be a real possibility.