A successful vaccine should lead to the

A successful vaccine should lead to the generation of long-lived plasma cells and memory B cells that are thought to be essential for sustained humoral immunity. However, during chronic infection, the persistence of viral estrone alters B cell differentiation into memory cells (Colineau et al., 2015). Memory B cells can be divided in 4 subpopulations: activated memory (AM, CD27+CD21 −), resting memory (RM, CD27+CD21+), intermediate memory (IM, CD27 −CD21+) and tissue-like memory B cells (TLM, CD27 −CD21 −) (Moir et al., 2008). AM and TLM B cells (the latter corresponding to anergic cells) are overrepresented in untreated HIV-infected patients (Moir et al., 2008; Pensieroso et al., 2013) and are associated with higher levels of viremia (Kardava et al., 2014). In contrast, RM cells that contribute to maintaining humoral responses, are decreased upon infection (Good et al., 2009; Moir and Fauci, 2013). Remarkably, HIV-specific B cells are enriched in TLM and AM B cell subsets but decreased in RM cells (Kardava et al., 2014). Compared to the levels in HIV-negative individuals, cART restores TLM and AM B cell proportions and only partially the RM compartment (Moir et al., 2008; Moir et al., 2010; Pensieroso et al., 2013). Although ECs do not clear the infection, studying their memory B cell responses could help understand the maintenance of long lasting humoral immunity in the presence of low to undetectable antigen loads. In ECs, RM and AM B cell proportions are higher compared to treated HIV-infected patients but no differences were observed concerning the percentage of TLM cells (Pensieroso et al., 2013). However, in ECs, the frequency of HIV-specific TLM B cells is reduced compared to treated HIV-infected patients (Buckner et al., 2016). Taken together, these results suggest that ECs preserve their memory B cell compartments but also exhibit features of viremic individuals (increased AM cells). Whether this preservation of the memory B cell subsets, in ECs, is associated with the maintenance and/or a higher frequency of HIV-specific memory B cells expressing various Ab subclasses remains an open question. In addition, potential correlations between HIV-specific memory B cell frequencies and the neutralization breadth in sera have not been investigated so far. Two studies previously analyzed potential correlations between Ab responses and Ab secreting cells (Bussmann et al., 2010; Doria-Rose et al., 2009). Bussman et al. asked whether the frequency of Env/gp120-specific B cells might correlate with the Ab titers to Env/gp120 protein (Bussmann et al., 2010) while Doria-Rose et al. studied the frequency of plasmablasts that spontaneously secret HIV-specific Abs and the breadth of neutralization (Doria-Rose et al., 2009). Both studies failed to observe any correlation between these HIV-specific B cell responses and the Ab profiles. In the present study, we characterized memory B cell responses in a cohort of ECs either positive or negative for the HLA-B*57 protective allele. We analyzed whether the preservation of B cell compartments might be linked to the capacity of B cells to secrete HIV-specific Abs. We compared B cell responses in HLA-B*57+ and HLA-B*57− ECs with either that of aviremic patients undergoing successful cART or HIV-negative individuals. We observed a global preservation of memory B cell compartments in ECs with a proportion of TLM comparable to what was observed in cART and HIV-negative individuals. Interestingly, HIV-specific B cells were detected in 82% of ECs. In contrast, only 7% of cART patients presented HIV-specific responses whereas all groups exhibited similar levels of Influenza-specific B cell responses. HIV-specific responses consisted mainly of IgG1 secreting B cells although HIV-specific IgG2 and IgG3 secreting B cells were detected in a third of ECs. Next we analyzed whether these B cell responses might correlate with the capacity of patients\' sera to neutralize HIV. For this purpose, we used mostly difficult-to-neutralize tier-2 transmitted/founder (T/F) viruses. 89% of sera from ECs neutralized at least one HIV strain tested and 8% blocked infection of at least 40% of difficult-to-neutralize tier-2 T/F viruses. Remarkably, among HLA-B*57+ ECs, the frequency of Env-specific memory B cells correlated positively with the capacity to neutralize T/F HIV strains, suggesting that these cells might contribute to the neutralizing responses in this group of ECs. Overall, through the analysis of Env-specific memory B cell frequencies, the isotype diversity and the neutralization breadth, our results reveal major differences between HLA-B*57+ and HLA-B*57− ECs.