Although these data indicate the potential effectiveness

Although these data indicate the potential effectiveness of passive immunotherapy by NAbs, the successful development of preventive HIV-1 vaccines requires a thorough understanding of how Nabs are induced during HIV-1 infection. The unusual maturation features of NAbs make them extremely difficult to induce and indicate that one of the most important challenges for vaccines development is to characterize well-defined targets that specifically stimulate neutralizing activity (Sadanand et al., 2016). The gp41 subunit is far more conserved than gp120, and the fusion machinery is common to all strains. We previously described a highly specific motif localized in a gp41 HIV-1 region, called 3S (Vieillard et al., 2005; Vieillard et al., 2016), localized between the N-terminal heptad repeat (HR) 1 and the HR2, that appears to be exposed to the surface in the trimeric pre-fusion structure of the HIV-1 envelope (Fig. S1), in line with recent resolve structures of the HIV-1 envelope trimer (Pancera et al., 2014; Lee et al., 2016). In an in vivo macaque model, immunization with a candidate vaccine based on the 3S motif induced non-neutralizing Abs, which limited CD4+ T-cell depletion, immune activation, and inflammation, thus achieving immune protection and restoring immune angiotensin receptor blockers (Vieillard et al., 2008, 2012). An alanine-scanning assay within the 3S motif of the viral gp41 protein showed that a tryptophan residue at position 614 (W614) is crucial for the virus entry (Petitdemange et al., 2013). The main reason could be that this region plays a key role in the formation of the six-helix bundled gp41 ectodomain core structure that imposes several kinetic and steric constraints responsible for the high degree of motif preservation, as previously reported (Gallo et al., 2003). Altogether, these data could explain the absence of detectable “3S” escape variants, and the remarkable conservation of the 3S motif within the gp41 (Vieillard et al., 2005; Potard et al., 2013). Next, we generated in mice a class of Abs against the 3S motif, called W614A-3S Ab that elicits neutralizing activity, against a panel of tier 1 and tier 2 viruses from clades A, B, C and E (Petitdemange et al., 2013). More recently, these data were confirmed in rabbit and macaque models (unpublished data are from Vieillard et al.). Our data are in accordance with Bradley et al. (2016) showing that amino-acid changes in gp41 membrane proximal region (MPER) induce viral neutralization sensitivity. Interestingly, we also determined that approximately 5% of HIV-1-infected progressor patients naturally produce neutralizing W614A-3S Abs (Petitdemange et al., 2013). In this study, we analyzed the neutralizing activity of W614A-3S Abs isolated from long-term non-progressor (LTNP) patients from the French ALT (“Asymptomatic Long-Term”) cohort (“Agence Nationale de Recherche sur le Sida” ANRS CO15). These HIV-1-infected individuals account for <0.4% of the total HIV population (Grabar et al., 1999). They maintain high CD4+ T-cell counts and remain therapy naïve. Here, we report an unusually high frequency of LTNP patients with W614A-3S Nabs. These Abs displayed neutralizing activities over a five-year follow-up period, which are correlated with low viral load, low viral reservoir, and high CD4+ T-cell responses. These data support the hypothesis that these specific Nabs play an important role in vivo in maintaining LTNP status.
Materials and Methods
Results
Discussion Here, we report that NAbs against the highly conserved 3S gp41 Env motif are more prevalent in LTNP HIV+ patients than in HIV progressor patients (23.5% vs 4.7%) (Gallo et al., 2003), indicating that this motif is likely associated with a lack of disease progression. Furthermore, W614-3S NAbs were detected predominantly in patients with low levels of viral load and viral DNA and high CD4+ T-cell counts and preserved T-cell function. The absence of effect mediated by anti-T20 Abs suggests that function associated with anti-W614A-3S NAb is certainly not a general property of NAbs, and support the hypothesis that W614A-3S NAbs provide immune benefits and may be associated with LTNP status. We can however not exclude that W614A-3S Abs develop preferentially under conditions of non-progression, such as high CD4+ T cells and low viral load.