NAbs occurring after initial infection with HIV

NAbs occurring after initial infection with HIV-1 are generally not associated with any clinical or biological benefits. Doria-Rose et al. (2010) suggested that the limited breadth of neutralization observed in whole-serum samples from LTNP patients maybe attributable to low levels of antigenic stimulation due to their undetectable viral loads. Indeed, several studies have demonstrated that the development of NAbs is significantly associated with duration of infection and high viral load and that NAbs do not protect against HIV-1 disease progression, whereas Freund et al. (2017) have recently shown the coexistence of potent NAbs and antibody-sensitive viruses in a viremic controller. These findings were consistent with a model in which antigenic stimulation drives the breadth of the NAb response (Euler et al., 2010; Piantadosi et al., 2009). Such a model, however, is not supported by our data. Notably, previous studies examined neutralizing activities in whole-serum samples and not in samples specifically prepared from highly conserved motifs of Env. Interestingly, the neutralizing activity of W614A-3S-specific Abs observed in the TZM-bl standard assay was greatly potentiated by targets expressing FcγRI, as previously observed for MPER-specific mAbs (Perez et al., 2009). The mechanism remains unclear, but our pre-positioning of the 3S motif at the cell surface, where it has been observed on the pre-fusion HIV envelope 3D structure (Fig. S1), may have facilitated its binding to FcγRI, thereby conferring a kinetic advantage for virus inhibition by W614A-3S Abs. Generally, this could be observed in Abs with epitopes exposed for at least a short time on an intermediate pre-fusion conformation of gp41 (Wyatt and Sodroski, 1998; Labrijn et al., 2003). FcγRI engagement may also stabilize a favorable orientation of Abs at the sterically constrained virus-cell interface to provide an additional kinetic advantage for a specific intermediate conformation of gp41. This will have to be investigated, however, this LY335979 is strengthened by the high conservation of the W614 position within the 3S motif of the gp41 in all LTNP tested (Table S1) (Potard et al., 2013), suggesting that W614A-3S Abs could recognize a “conformational intermediate epitope”, mimic by the W614A-3S peptide. Thus, the generation of W614A-3S Abs is certainly not the result of mutated W614A-3S virus production, which are non-infectious (Petitdemange et al., 2013), but could be associated with an increased Ab binding and/or neutralizing breadth. Although rare on CD4+ lymphocytes, FcγRs are highly expressed by macrophages and dendritic cells, which are involved in the sexual transmission and early establishment of long-lived viral reservoirs25. We observed greater neutralizing activity in macrophages (MDMs) than in TZM-bl cells, as previously reported for HIV and SIV infections with MPER mAbs (Perez et al., 2013; Lederle et al., 2014; Su and Moog, 2014; Zhuge et al., 1997; Ruppach et al., 2000). Remarkably, the polyclonal neutralizing efficiency of W614A-3S NAbs against the BaL HIV strain in MDMs was highly potent, with levels similar to or higher than those observed with neutralizing mAbs. These polyfunctional capacities may be extremely useful for a prophylactic vaccine. To date, most studies have analyzed NAbs cross-sectionally, and only a few have conducted long-term follow-up of neutralizing responses according to HIV-1 disease outcome (Cecilia et al., 1999; Chaillon et al., 2012). Here, we observed that the neutralizing activity of purified W614A-3S Abs increased in all LTNP patients at 5years post-enrollment. As the purified W614A-3S Abs corresponded to a mixture of mAbs, as suggested by the variation in term of CDR-H3 motifs, it is tempting to speculate that affinity maturation leading to the selection for the most efficient NAbs occurred with time. Notably, W614A-3S Ab-mediated neutralizing activity was both inversely correlated with viral load and viral DNA, in accordance with the enhanced clearance of infected cells after passive transfer of NAbs in SHIV-infected macaques (Lu et al., 2016; Liu et al., 2016). Notably, W614A-3S Ab neutralizing activity decreased in LTNP patients with persistent viral loads, perhaps due to modifications of Ab/epitope recognition following viral escape mechanisms over time, as described (van Gils et al., 2010). Our results suggest that the durability of certain NAbs may be a major clue to the mechanisms of long-term non-progression. To date however, the mechanism to explain the presence of W614A-3S NAb remains unclear, we can however hypothesized that W614A-3S Abs recognized an “intermediate conformational epitope” within the highly conserved 3S motif of the gp41, which is mimic by the W614A-3S peptide. In accordance with the substantial conformational changes in gp41 used facilitate viral entry (Wyatt and Sodroski, 1998), we can supposed that this “intermediate conformational epitope” should be exposed for at least a short time on an intermediate pre-fusion conformation of gp41. A complete characterization of W614A-3S NAb could be very informative.