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  • The immunologic data demonstrate the

    2018-11-13

    The immunologic data demonstrate the broad cross-reactivity of vaccine-induced V3 Abs (Fig. 1 and Table 2) and recapitulate studies documenting the ability of many V3 mAbs to cross-react immunologically with diverse V3 peptides (Gorny et al., 1997), to capture virions from multiple subtypes (Nyambi et al., 2000), and to mediate cross-clade neutralization, though V3 mAbs preferentially neutralize sensitive Tier 1 viruses (Gorny et al., 1992; Conley et al., 1994; Corti et al., 2010; Hioe et al., 2010; Mouquet et al., 2011). Extensive structural data have demonstrated that glycan-independent human V3 mAbs target the mid-region (or “crown”) of the V3 loop (Stanfield et al., 2004; Burke et al., 2009; Gorny et al., 2009; Jiang et al., 2010). Sites 307 and 317 in the crown are both part of the Sepantronium Supplier core of the V3 epitope recognized by these mAbs. These residues are highly conserved, with I307 and F317 each present in eight of nine HIV subtype consensus sequences (Lynch et al., 2009), but whereas position 307 is a major contact residue, position 317 has minor or no contact with most V3-specific human mAbs (Stanfield et al., 2004, 2006; Burke et al., 2009; Jiang et al., 2010). This extensive body of literature is augmented by studies of two mAbs, CH22 and CH23, which were isolated from vaccinees in the RV135 trial who received a vaccine regimen identical to that of RV144 (Montefiori et al., 2012). The epitopes recognized by these two mAbs are glycan-independent and react with V3 linear peptides in the crown of the V3 loop containing I307 and F317 (shown in bold and underlined: RKRHIGPGRAYTT and NTRTSNIGPGQVY, respectively). Notably, these are not highly mutated Abs, having VH mutation frequencies of 3.7% and 4.5%, respectively, and each has a CDR H3 of 11 amino acids, characteristics similar to those found commonly in human Abs (Tiller et al., 2007). CH22 administered to macaques was able to protect against infection with SHIV BaL P4 (Haynes BF and Santra S, personal communication), extending similar work reported earlier (Watkins et al., 2011) and providing new data on the breadth of reactivity and the protective effects of V3 Abs. These data add support for the hypothesis that vaccine-induced V3-specific (and/or V2 specific) Abs contributed to the reduction in infection rate in vaccinees. While it is known that V3 Abs are induced early after infection and can drive rapid viral escape (Tomaras et al., 2008), the fact that the sieve analysis showed a difference between breakthrough viruses of vaccine and placebo recipients suggests that the V3 Abs exerted immune pressure in the vaccinees and therefore the vaccine-induced Abs had a biologic effect on the viruses that emerged in the setting of human infection. The results of the RV144 study, identifying inverse correlates of risk related to levels of both V2 and V3 Abs (Haynes et al., 2012; Gottardo et al., 2013) recapitulate some of the many V2 and V3 commonalities. First, both crystallographic and cryo-EM studies of gp120 have shown that V2 and V3 are closely packed together at the apex of the envelope trimer (Bartesaghi et al., 2013; Julien et al., 2013; Lyumkis et al., 2013). Both V2 and V3 induce highly cross-reactive Abs in HIV-infected individuals (Gorny et al., 1997, 2012); and V2 and V3 induce both glycan-independent (Gorny et al., 1997, 2002) and glycan-dependent Abs (Pejchal et al., 2011). Most striking, perhaps, are the similarities revealed by the RV144 sieve analyses of V2, published earlier (Rolland et al., 2012), and the sieve analysis related to V3, described above. These studies suggest, independently, that immune pressure is exerted on viruses that match the vaccine at V2 position 169 and also at V3 position 307 (Fig. 2A). Vaccine efficacy for viruses matched with the vaccine at 169 is 48% (p=0.004); VE for viruses matched with the vaccine at 307 is 52% (p=0.004). The analogy continues to hold from the sieve analyses of site 181 in V2 and site 317 in V3 (Fig. 2B). For these latter positions, there was an atypical sieve Sepantronium Supplier effect with a VE of 78% (p=0.003) against viruses with mutations at V2 site 181 (I181X), and a VE of 85% (p=0.004) against viruses with mutations at V3 site 317 (F317X).