P09-12. Autologous neutralizing antibodies in early subtype C HIV-1 infection target variable regions of envelope and drive multiple pathways of viral escape

Specificity of the autologous neutralizing antibody response

“…This suggestion was confirmed using chimeras constructed between envelopes derived from early subtype C infection [11*], and by examining neutralization escape variants which also implicated the V1V2 region as a target of AnAbs [11*,31,32,33]. Confirmation of the role of V1V2 as an AnAb target comes from the isolation of anti-V1V2 antibodies recognizing glycan-dependent epitopes from B-cell hybridomas of a subtype C infected individual [33]. The V1V2 region therefore appears to be commonly immunogenic in early HIV-1 and SHIV infections.…”

“…In subtype C infection, a similar approach using chimeric Env derived from transmission pairs suggested that V1V2 may contain AnAb epitopes in some cases, in addition to the more general role of V1V2 in shielding neutralization determinants [29]. This suggestion was confirmed using chimeras constructed between envelopes derived from early subtype C infection [11*], and by examining neutralization escape variants which also implicated the V1V2 region as a target of AnAbs [11*,31,32,33]. Confirmation of the role of V1V2 as an AnAb target comes from the isolation of anti-V1V2 antibodies recognizing glycan-dependent epitopes from B-cell hybridomas of a subtype C infected individual [33].…”

“…The V4 region has been proposed to contribute to the formation of quaternary epitopes in conjunction with the C3 region in subtype C viruses [11*,35] (see below for details), but independently the V4 does not appear to be a significant AnAb target, although changes in this region may mediate neutralization escape [36]. Similarly, the use of chimeras suggested only a marginal role for V5 as a target of AnAbs in early HIV-1 infection [11*], however again changes within the V5 may effectively mediate escape from AnAbs [32,33]. The mechanism whereby such escape occurs remains to be defined, but it may be via modulation of proximal epitopes [32,33] with which V5 interacts, such as the adjacent CD4bs [37].…”

“…Similarly, the use of chimeras suggested only a marginal role for V5 as a target of AnAbs in early HIV-1 infection [11*], however again changes within the V5 may effectively mediate escape from AnAbs [32,33]. The mechanism whereby such escape occurs remains to be defined, but it may be via modulation of proximal epitopes [32,33] with which V5 interacts, such as the adjacent CD4bs [37]. …”

“…In contrast, the identification of 4E10-resistant variants in an HIV-1 infected individual exhibiting an anti-MPER antibody response suggested immune escape from AnAb responses targeting this region [46]. Analysis of neutralization escape in subtype C infected individuals suggested a role for the ectodomain of gp41 in neutralization escape though it was not clear whether the AnAbs in this case targeted gp41 directly or whether escape occurred via modulation of distal epitopes [33]. It is noteworthy that in the above cases, anti-gp41 antibody pressure was observed after one year of infection and considerably delayed compared to the primary autologous neutralization response.…”